Management of stable COPD: An update

Abstract

Chronic obstructive pulmonary disease (COPD) is a major problem for public health worldwide and an important cause of morbidity and mortality at the global level. Its burden is expected to increase progressively in the next years. This article summarizes the most current aspects of the non-pharmacological and pharmacological treatment of stable COPD. Non-pharmacological therapies, such as smoking cessation, vaccinations, oxygen therapy and pulmonary rehabilitation are covered briefly. Drug classes covered are short acting beta agonists (SABA), short acting muscarinic antagonists (SAMA), long acting beta agonists (LABA), long acting antimuscarinics (LAMA), inhaled corticosteroids (ICS), LABA/ICS combinations and specific phosphodiesterase (PDE4) inhibitors.

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352 Current Respiratory Medicine Reviews, 2013, 9, 352-359
Management of Stable COPD: An Update
Alexandru Corlateanu*,1, Gloria Montanari2, Alexandros G. Mathioudakis3, Victor Botnaru1 and
Nikolaos Siafakas4
1Department of Respiratory Medicine, State University of Medicine and Pharmacy “Nicolae Testemitanu”, Chisinau,
Moldova, ERS National Delegate for Moldova, GOLD National Leader for Moldova, Republic of Moldova
2Department of Respiratory Diseases, Department of Medical and Surgical Sciences for Children & Adults, University
of Modena and Reggio Emilia, Modena, Italy
3Aintree University Hospitals NHS Trust, UK
4University General Hospital, Dept. of Thoracic Medicine, 71110 Heraklion, Greece
Abstract: Chronic Obstructive Pulmonary Disease (COPD), being a major cause of morbidity and mortality worldwide, is
a major problem for public health. It is predicted that its burden will continuously expand over the next years. This article
is an up-to-date review of both non-pharmacologic and pharmacologic management of COPD, which is now based on
new staging systems, able to predict prognosis and the response to different treatment approaches. Non-pharmacologic
therapies, such as smoking cessation, vaccinations and pulmonary rehabilitation are covered briefly. Current
pharmacologic management covers short acting beta-agonists (SABA), short acting muscarinic antagonists (SAMA), long
acting beta agonists (LABA), long acting antimuscarinics (LAMA), inhaled corticosteroids (ICS), LABA/ICS
combinations, xanthines, specific phosphodiesterase 4 (PDE4) inhibitors and oxygen therapy.
Keywords: Chronic obstructive pulmonary disease (COPD), disease management, pharmacotherapy, phenotypes,
rehabilitation.
INTRODUCTION
Chronic Obstructive Pulmonary Disease (COPD), being a
major cause of morbidity and mortality worldwide, is a
major problem for public health. It is predicted that its
burden will continuously expand over the next years. COPD
is currently the fourth leading cause of chronic morbidity
and mortality globally. It has been projected that COPD
prevalence will progressively increase and it will be the third
leading cause of mortality by 2020 [1]. In the last Global
Initiative for Chronic Obstructive Pulmonary Disease report
(GOLD2014) [2], the scientific committee suggested the
following definition of COPD: a common preventable and
treatable disease characterized by persistent airflow
limitation that is usually progressive and associated with an
enhanced chronic inflammatory response in the airways and
the lung to noxious particles or gases. Exacerbations and
comorbidities contribute to the overall severity in individual
patients. The complexity of COPD and its heterogeneous and
multisystemic character was recognized in the last decade.
Non-pharmacologic and pharmacologic treatment should
be guided by COPD severity and aim to control symptoms,
decrease exacerbations, and improve patient function and
quality of life [3]. Both non-pharmacologic and pharmaco-
logic interventions are essential to the management of stable
COPD. Non-pharmacologic therapy includes: smoking
*Address correspondence to this author at the State University of Medicine
and Pharmacy “Nicolae Testemitanu”, Stefan cel Mare street 165, 2004
Chisinau, Republic of Moldova; Tel: +37322205132;
E-mail: alexandru_corlateanu@yahoo.com
cessation, reduction of other risk factors, vaccinations, and
pulmonary rehabilitation.
Inhaled bronchodilators (beta agonists and anticholinergics)
are currently the mainstay of pharmacologic management of
stable COPD [4]. Inhaled bronchodilators can be used alone
or in combination with inhaled glucocorticoids depending on
the severity of COPD and risk of exacerbations. The goals of
the treatment in stable COPD include symptomatic relief,
improvement of the health status and exercise tolerance,
prevention of disease progression and exacerbations, and
thus mortality.
This article summarizes the most current aspects of both
non-pharmacologic and pharmacologic treatment of stable
COPD.
ACTUAL COPD ASSESSMENTS: SEVERITY VERSUS
CLINICAL PHENOTYPES VERSUS MULTILATERAL
ASSESSMENT
There are three well-known and widely accepted
approaches to the assessment of COPD: GOLD assessment
of severity, multilateral evaluation and phenotyping. The
comparative characteristics of these three approaches are
presented in Table 1.
In the GOLD 2011 report [5], the scientific committee
proposed a new combined staging system with evaluation of
(1) the symptomatic status (dyspnoea) as assessed by
Medical Research Council (MRC) scale, (2) the physiologic
status with the assessment of airflow limitation severity by
FEV1 and (3) the health status assessing the impact of
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Management of Stable COPD: An Update Current Respiratory Medicine Reviews, 2013, Vol. 9, No. 6 353
disease on patients daily lives by the COPD Assessment Test
(CAT), and (4) exacerbation frequency via evaluation of the
risk of exacerbations.
More than 15 multilateral indices were proposed for the
assessment of COPD. The most useful is BODE index, which
was proposed by Celli and Cote in 2004 [6]. In BODE were
included 3 variables which are better predictors of mortality
than FEV1 (BMI, dyspnea assessed by Medical Research
Council scale and exercise capacity evaluated by 6 minute
walking test). The BODE index may be used to assess the risk
of death or hospitalization among patients with COPD [6]. Also,
the BODE index can predict the exacerbation frequency [7].
Given the correlation between the severity of disease and
mortality of COPD patients, the BODE index is now suggested
as the mainstay of the classification and management of COPD
[8].
Multiple studies demonstrated that COPD patients with
similar airflow limitation had diverging clinical characteristics,
including symptoms, comorbidities and predicted mortality [9].
Phenotyping of COPD patients may rely on clinical and
physiological manifestations, imaging, assessment of patient-
related outcomes (health related quality of life), COPD
comorbidities, exacerbations and systemic inflammation [10].
Recently, it was demonstrated that roflumilast improves
lung function and reduces the frequency of exacerbations in
patients with predominantly bronchitic symptoms and severe
airflow limitation, a specific clinical COPD phenotype [11-13].
This is the first proven personalised treatment based on
phenotypic characteristics of COPD [12, 13]. It suggests that
multiple phenotypic subgroups of patients exist within the broad
range of COPD and specific personalised therapies might
improve the disease management [14].
One of the first attempts to implement phenotyping in
everyday clinical practice was made in Spanish Guidelines for
COPD [15, 16]. There were proposed four phenotypes that
determine differential treatment: (1) non-exacerbator, with
emphysema or chronic bronchitis; (2) mixed COPD-asthma; (3)
exacerbator with emphysema; (4) exacerbator with chronic
bronchitis [16]. BODE multilateral index for the assessment of
COPD severity was also included in the classification.
NON-PHARMACOLOGIC TREATMENT
Smoking Cessation
Smoking cessation is considered the most important
intervention for all COPD patients who smoke regardless of
the level of disease severity [3]. Smoking cessation is an
essential part of the treatment of COPD, because it can
reduce the accelerated pulmonary function decline rate of
smokers with COPD, as it was clearly shown in the Lung
Health Study [17].
Interventions that assist smoking cessation include
clinician advice and encouragement, nicotine replacement
therapy, bupropion, varenicline and nortriptyline, and
counseling [2]. The best cessation rates can be achieved
when counseling is combined with medication therapy in
comparison with each strategy separately [18].
Vaccinations
Exacerbations of COPD are the most important adverse
events in the progression of COPD. The most common cause
of COPD exacerbations is infection [19]. Vaccinations can
prevent some infections and should be offered to patients
with stable COPD.
Pneumococcal vaccine and annual influenza vaccine
should be offered to all patients with COPD. Pneumococcal
vaccine significantly reduces the risk of community
acquiring pneumococcal pneumonia in patients with COPD
[20]. Influenza vaccination significantly reduces the risk of
acquiring influenza-related acute respiratory infections in
patients with COPD, especially in patients with severe
airflow obstruction [20].
Pulmonary Rehabilitation
Pulmonary rehabilitation is recognized as a core component
of the management of patients with chronic respiratory disease
[21]. Pulmonary rehabilitation has been clearly demonstrated to
decrease dyspnea and health care utilization, increase exercise
capacity and improve quality of life in individuals with COPD
[22]. Also pulmonary rehabilitation may decrease hospital
admissions and mortality [23].
Pulmonary rehabilitation program includes supervised
exercise training, self-management education, and
psychosocial support [21]. In all stages of COPD, exercise
training has been demonstrated to be efficient in a number of
outcomes of patients with COPD, such as improvement of
exercise tolerance, muscle strength, quality of life and
decrease of dyspnoea and fatigue [24]. Pulmonary
rehabilitation is a well-recognised therapy that should be
available to all patients with symptomatic COPD, and
exercise training represents the cornerstone of a pulmonary
rehabilitation programme [21, 24].
Table 1. Markers Used in Different Approaches for COPD Assessment
Markers
GOLD 2011
Multilateral Indices (BODE)
Phenotyping
Symptomatic
Dyspnea assessed by Medical Research Council scale
Dyspnea assessed by Medical
Research Council scale
Symptoms
Physiologic
FEV1
FEV1, BMI, exercise capacity
evaluated by 6 minute walking test
FEV1
Health status
The COPD Assessment Test (CAT)
-
-
Exacerbations
Evaluation of the risk of exacerbations
-
Evaluation of the risk of
exacerbations
Imaging
-
-
X-Ray, HRCT

354 Current Respiratory Medicine Reviews, 2013, Vol. 9, No. 6 Corlateanu et al.
Pulmonary rehabilitation represents an ideal opportunity
to facilitate chronic disease self-management [25]. Chronic
disease self-management includes methods designed to:
facilitate smoking cessation; optimise pharmacotherapy;
assist with early identification and treatment of acute
exacerbations; manage acute dyspnoea; increase physical
activity; improve body composition; promote mental health;
facilitate advance care planning and establish a social
support networks [25].
PHARMACOLOGIC TREATMENT
Bronchodilators
Bronchodilators have been the mainstay of management
of COPD, which is characterised by a substantially
irreversible airflow obstruction [1]. Bronchodilators include
beta agonists, anticholinergics, and theophylline, which is
used less often. Inhaled agents are preferred to oral because
of the reduction in systemic side effects [26].
Besides improving dyspnea through their direct
bronchodilatory effects, beta agonists and anticholinergics
also appear to work by reducing static and dynamic
hyperinflation. This probably explains why long-term
improvements in symptoms and exercise capacity may be
seen without clear changes in the FEV1 [27].
Short-Acting Bronchodilators
Short-acting beta agonists (SABA) are the most widely
used bronchodilators in the management of COPD, with
salbutamol being the most common among them. Short-
acting beta agonists appear to be as effective when used on
an as needed basis as when used regularly, on the contrary to
other bronchodilators [28]. The advantage of short-acting
beta agonists is their rapid onset of action.
Short-acting muscarinic antagonists (anticholinergics):
Ipratropium has been demonstrated to reduce dyspnea,
increase exercise tolerance, and improve gas exchange in
patients with COPD.
Short-acting beta agonists and short-acting muscarinic
antagonists (SAMA) can be used alone or in combination.
The combination of a short-acting beta agonist plus a short-
acting anticholinergic is often preferred because combination
therapy can achieve a greater bronchodilator response than
either one alone [29].
Long-Acting Bronchodilators
Two classes of long-acting inhaled bronchodilators are
available—long-acting β2-agonists (LABAs) and long-acting
muscarinic antagonists (LAMAs).
Long-acting β2-agonists, salmeterol and formoterol
provide 12 hour bronchodilation. Ultra-LABA provide 24
hour bronchodilation and include indacaterol, olodaterol,
vilanterol (recently approved as a component of a
combination drug), carmoterol and some new agents [30].
Salmeterol and Formoterol
Salmeterol significantly improved lung function (including
reduction in lung hyperinflation) and dyspnoea, increased
exercise capacity and enhanced health related quality of life
[31]. In the largest trial of salmeterol, Toward a Revolution in
COPD Health (TORCH), salmeterol significantly decreased
exacerbation rates, improved lung function, and improved
health-related quality of life compared to placebo [32].
Formoterol has been demonstrated to provide a rapid onset
bronchodilatation that occurs within minutes after inhalation
[30], which is comparable with the effect of SABA. The rapid
onset of action and prolonged, potent bronchodilatory effect of
formoterol suggest a drug effective for both quick relief and
prolonged effect [33]. In COPD patients, formoterol induces a
significant spirometric improvement lasting for 12h [34].
Despite these positive characteristics, it appears to be inferior to
salmeterol in terms of health related quality of life (HRQoL)
scores and its ability to reduce the rate of COPD exacerbations
[33].
Indacaterol
Indacaterol is the first ultra-long-acting β2-agonist (ultra-
LABAs) approved for the treatment of COPD, that allows for
once-daily administration [35]. It has a rapid onset and
prolonged action, with an onset of action in five minutes and a
bronchodilatory effect that lasts for 24 hours. In long-term
clinical trials in patients with moderate to severe COPD,
indacaterol 150 or 300 µg improved lung function significantly
more than placebo, and improvements were also significantly
greater than twice daily formoterol 12 µg or salmeterol 50 µg,
and noninferior to tiotropium bromide 18 µg [36, 37].
Indacaterol improves dyspnoea and health related quality of life,
reduces the use of rescue medications significantly more than
placebo, salmeterol or tiotropium bromide, and the degree of
improvement in these endpoints is similar to or greater than that
achieved with formoterol [38].
Long-acting and ultra-long-acting β2-agonists induce
considerable improvements in FEV1, reduce dynamic
hyperinflation, and improve exercise tolerance, determining
amelioration in dyspnea and health-related quality of life
[30]. Moreover, they reduce the rate of COPD exacerbations
[39].
Long-Acting Muscarinic Antagonists
Long-acting muscarinic agents (or long-acting
anticholinergic medications) include tiotropium, aclidinium and
glycopyrronium.
Tiotropium
Tiotropium is a once-daily, long-acting muscarinic
antagonist [30]. Understanding Potential Long-Term Impacts on
Function with Tiotropium(UPLIFT), a four year randomised
clinical trial which compared inhaled tiotropium versus placebo,
demonstrated an improvement in lung function and quality of
life, with a concomitant decrease of the risk of exacerbations
[40]. However, it does not decrease the rate of decline of
pulmonary function. A recent meta-analysis has shown that
tiotropium handihaler may prolong the survival of COPD
patients [41].
Aclidinium
Aclidinium bromide is a recently developed LAMA
administered twice daily. In a 12-week, double-blind study,
200 and 400 mcg of aclidinium significantly reduced night-

Management of Stable COPD: An Update Current Respiratory Medicine Reviews, 2013, Vol. 9, No. 6 355
time/early morning symptoms and daily rescue medication use
in patients with COPD [42]. Besides, it has noticeably improved
health related quality of life and decreased dyspnea of patients
with moderate to severe COPD [43].
Glycopyrronium
Glycopyrronium is a novel once daily LAMA. A 26-week
double-blind treatment with 50 µg of glycopyrronium bromide
once daily induced clinically significant bronchodilation with
rapid onset and maintained for 24h, throughout the study [44].
Moreover, it provided a significant improvement in dyspnea at
26 weeks compared to placebo, which was accompanied by a
significant improvement in health-related quality of life and
reduced rescue medication use.
LABA versus LAMA
The efficacy of LABAs and LAMAs has been compared in
multiple meta-analyses and randomized trials [36, 45].
The Prevention of Exacerbations with Tiotropium in COPD
(POET-COPD) trial was specifically designed to directly
compare the effects of tiotropium with those of salmeterol on
the risk of moderate and severe exacerbations [45]. Tiotropium
increased the time to the first severe exacerbation of COPD,
reduced the risk of developing an exacerbation by 17 percent
(hazard ratio 0.83, 95% CI 0.77-0.90) and reduced the annual
number of severe exacerbations compared to salmeterol [45]. It
is important to mention that it was not a direct comparison of a
long-acting β2-agonist with a long-acting anticholinergic agent,
since concomitant medications were allowed; more than 50% of
the patients were receiving, on a regular basis, inhaled
glucocorticoids which also reduce exacerbations.
Another study compared indacaterol, a once daily inhaled
beta agonist, versus tiotropium, in patients with moderate to
severe COPD. Similar outcomes regarding pulmonary function,
dyspnea and quality of life were obtained in this trial [36].
Seven clinical studies including a total of 12,223 participants
with COPD were included in a meta-analysis, comparing
tiotropium with salmeterol, formoterol, or indacaterol [46].
Tiotropium was more effective than LABAs in preventing
COPD exacerbations and disease-related hospitalisations,
although there were no statistical differences between group in
overall hospitalisation rates or mortality. No significant
difference was found in improvements in the quality of life
between tiotropium and the LABAs either. Symptom
improvement and changes in lung function were similar
between the treatment groups.
Until recently, LAMAs were preferred over existing LABAs
because of their superiority regarding most of the significant
endpoints. However, after the development of novel once daily
LABAs and twice daily LAMAs, the initial selection of a long
acting bronchodilator is often based on clinical response of each
patient, co-morbidities, and side effects [2].
Dual (Double) Bronchodilator Therapy
A recent trial demonstrated that the combination of
LABA and LAMA is potentially effective in symptoms
control of patients with stable moderate COPD sub-
optimally controlled by tiotropium monotherapy [47].
Multiple studies showed a superior bronchodilation effect of
a LABA and LAMA combination compared to individual
agents alone, in patients with moderate to severe COPD [30].
Moreover, dual bronchodilator approach induced greater
improvements in patient-centred outcomes such as dyspnoea,
symptoms, rescue medication use and health-related quality
of life than individual drugs [48]. LABAs and LAMAs
directly act on airway smooth muscle working through
different pathways [30]. The combination of bronchodilators
of different classes seems a convenient way of delivering
treatment and obtaining better results for patients with
inadequate symptoms control by maintenance monotherapy
[2].
A new “dual” bronchodilator, with both antimuscarinic
and beta2-adrenergic activity combined in a single molecure,
was recently launched [49]. It was shown to have a rapid
onset of action and a potent bronchodilatory effect in
moderate and severe COPD, while it appears to be safe and
well-tolerated [50].
This approach can potentially offer several advantages
over combination therapy of two separate drugs: the benefit
of delivering a fixed ratio into every region of the lung
reducing the complexity of combination inhalers, a single
pharmacokinetic profile, a uniform ratio of activities at the
cellular level and a simplified clinical development
programme [30].
Xanthines
A meta-analysis of 20 randomized controlled trials
demonstrated that theophylline has a modest effect on FEV1
and forced vital capacity (FVC) and slightly improves
arterial blood gas tensions compared to placebo, in moderate
to severe COPD [51]. Improvement in exercise performance
depended on testing method. The use of xanthines is limited
by the risk of toxicity and multiple adverse reactions (central
stimulation, gastric secretion, diuresis and arrhythmias) [30].
The development of newer xanthines, such as
bamiphylline, acebrophylline, and doxofylline, for the
treatment of COPD, was carried out in anticipation that such
drugs would have a greater efficacy than theophylline but
with an improved side-effect profile [30]. Doxofylline has
been shown to have a better efficacy (combining
bronchodilator and anti-inflammatory properties) and fewer
side effects than theophylline [52].
Inhaled Corticosteroids
Beclomethasone, budesonide and fluticasone are the
commercially available inhaled corticosteroids (ICS) for the
treatment of COPD. In COPD, inhaled glucocorticoids are
used as part of a combined regimen, but should not be used
as monotherapy for COPD. ICS therapy decreases
exacerbations and modestly slows the progression of
respiratory symptoms, meanwhile it has a minimal or no
impact on lung function and mortality [53].
Numerous studies have proved that ICS therapy decreased
the risk of exacerbation compared to placebo [54, 55].
Furthermore, it was demonstrated that ICS therapy slowed the
progression of respiratory symptoms modestly [32] and slowed
the rate of decline of health-related quality of life [55].

356 Current Respiratory Medicine Reviews, 2013, Vol. 9, No. 6 Corlateanu et al.
Soriano et al. reported that ICS therapy did not modify the
FEV1 decline rate [56]. A Cochrane analysis [55], which
examined 55 primary studies with 16,154 participants, also
demonstrated that long-term use of ICSs (> 6 months) did not
consistently decrease the rate of decline in FEV1 in COPD
patients. Moreover, no significant difference was found in
mortality rate with the use of ICS as a mono-component
compared to placebo [55, 57]. New studies reassure the
possibility of osteoporosis secondary to ICS [58].
Bronchodilators Plus Inhaled Glucocorticoids
Combined inhalers include the twice-daily fluticasone-
salmeterol, budesonide-formoterol and mometasone-formoterol
combinations and a once daily dry powder inhaler, cont-
aining fluticasone furoate and vilanterol. Inhaled glucocorti-
coids are traditionally used in combination with a long-
acting bronchodilator for patients, who have significant
symptoms or frequent exacerbations, despite an optimal
bronchodilator regimen [59].
The efficacy of LABA/ICS combinations in COPD has
been well supported by some large trials [32, 60].
LABA/ICS combinations have been shown to improve lung
function and health related quality of life and to reduce
exacerbations in COPD patients.
Treatment with ICS/LABA is associated with a
significant increase ofthe pre- and post-bronchodilator FEV1
difference, the mean change in health related quality of life
and with a significant decrease in the dyspnea score
compared to treatment with LABAs alone [32].
Several randomized clinical trials have demonstrated that
LABA/ICS combinations reduce the risk of exacerbation by 10-
20% beyond that achieved by inhaled LABA alone [32, 60]. A
meta-analysis of 18 randomized controlled trials demonstrated a
beneficial effect of the LABA/ICS combination over LABA
alone, on the frequency of moderate, but not severe COPD
exacerbations [61]. It was recently suggested that ICSs in
combination with LABAs might also reduce cardiovascular
disease and all-cause mortality [59].
Triple Therapy
The triple inhaler therapy with a long-acting beta agonist
plus an inhaled glucocorticoid plus a long-acting
anticholinergic is often used in patients with severe COPD.
The benefits of triple therapy are confirmed by the UPLIFT
study [40]. The addition of tiotropium to patients receiving a
LABA and an ICS as usual care significantly improved
pulmonary function, decreased the rate of exacerbations, and
improved health related quality of life. More recently, it was
pointed out that triple therapy provides further improvements in
post-bronchodilator FEV1 and quality of life from baseline
compared to LAMA monotherapy on patients with severe and
very severe COPD [47].
Systemic Corticosteroids
Long-term systemic glucocorticoid therapy is not
recommended, even for severe COPD, because of the
significant side effects (most frequent are osteoporosis and
diabetes) and evidence of increased morbidity and mortality
with this treatment [62].
Inhibitors of the Phosphodiesterase 4
Roflumilast, an oral phosphodiesterase 4 inhibitor,
significantly improved pre-bronchodilator FEV1 and reduced
the rate of moderate to severe exacerbations (17 percent
[95%, CI 8-25]) in a 52 week, randomized trial of 3091
patients with COPD [13].
Roflumilast can be recommended for patients with
COPD with severe airflow limitation, symptoms of chronic
bronchitis and frequent exacerbations, whose disease is not
adequately controlled by long-acting bronchodilators [12,
13]. Roflumilast provides additional benefits when combined
with other respiratory medications. Roflumilast is the first-
in-class phosphodiesterase 4 inhibitor used as an add-on
therapy in patients with moderate to severe COPD and
frequent exacerbations who are already receiving a long-
acting bronchodilator. The effect of roflumilast when given
as additional therapy to COPD patients already taking long-
acting bronchodilators and ICS is currently not known.
Mucoactive Agents
Thick secretions can be a major problem in patients with
COPD, but there is little evidence that thinning or increasing
the clearance of sputum induces clinical improvement. A
recent Cochrane review has shown that treatment with a
mucolytic may produce a small reduction in acute
exacerbations, but may have little or no effect on the overall
quality of life [63]. Thus, mucoactive agents are not accepted
as routine care for patients with stable COPD [2].
Chronic Antibiotic Therapy
Chronic antibiotic therapy is generally not indicated by
guidelines for the patients with stable COPD [2]. However,
certain antibiotics, macrolides in particular, may have anti-
inflammatory and immunomodulatory activity in addition to
their antibiotic effect.
Long-term treatment with macrolides was asserted to
reduce COPD exacerbations in doses lower than bactericidal
doses [64]. However, the risk of microbial resistance
associated with the long-term use of azithromycin in patients
with COPD must be considered as part of the risk–benefit
ratio of this treatment. In addition, the effect on microbial
resistance in the community is still unknown [65].
Oxygen Therapy
Many patients with stable severe COPD have chronic
hypoxemia. Long-term oxygen therapy should be prescribed
for all patients with stable COPD, with chronic hypoxemia at
rest (PaO2 ≤55 mmHg or SpO2 ≤88 percent) [2]. The
detection of hypoxia is of great importance because long-
term oxygen therapy improves survival, severe resting
hypoxemia and quality of life in patients with COPD [66,
67].
Therapeutic Strategies in Stable COPD
New guidance for the management of COPD becomes
more complex, but can be simultaneously used by
respiratory doctors at a global level. This up-to-date
approach will potentially facilitate a more accurate risk

Management of Stable COPD: An Update Current Respiratory Medicine Reviews, 2013, Vol. 9, No. 6 357
stratification of COPD patients and a better understanding of
disease pathophysiology and phenotypes. It may eventually
help to develop a more targeted therapy and an improved
management of COPD patients.
Table 2 represents a comparison of the main differences
between GOLD 2014 guidelines [2] and Spanish Guideline
for Treatment of stable COPD [16] (Gula Espanola de la
EPOC - GesEPOC), some of which are described below.
The use of bronchodilators is central to the management
of COPD. Management of non-exacerbator phenotype, with
emphysema or chronic bronchitis is very similar to GOLD A
and B stages. Short-acting beta-agonists are used on an as-
needed basis or regularly for prevention of symptoms in the
early stages or in COPD patients with a low symptom
burden. Long-acting bronchodilators should be used as a first
therapeutic option in the treatment of all COPD patients with
permanent symptoms who regularly require short acting
bronchodilators, because they provide better control of the
symptoms and improve quality of life as well as pulmonary
function and exercise tolerance, while also reduce
exacerbations. The choice between LABA and LAMA
depends on the availability of medication and the patient’s
response. For patients whose symptoms are not controlled by
a LABA or LAMA, combination of these is recommended.
The basis of treatment of exacerbator phenotype with
emphysema (air traping, dyspnoea, low body mass index) is
long-acting bronchodilators and in more severe cases triple
therapy (LAMA+LABA+ICS) can be also used.
Exacerbator phenotype with chronic bronchitis
(bronchitic symptoms) should be treated with long-acting
bronchodilators. The addition of ICS or/and roflumilast is
suggested in severe cases.
The updated version of GOLD Strategy reports that
regular treatment with ICS improves symptoms, lung
function and quality of life and increases the rate of
exacerbations in COPD patients with an FEV1 < 60%
predicted [2]. Therefore, ICSs are recommended in
combination with LABAs or, alternatively, with LAMAs for
exacerbators (≥ 2 exacerbations or ≥ 1 exacerbation leading
to hospital admission) who have few symptoms (GOLD C
stage) and also for exacerbators who have significant
symptoms (GOLD D stage). Moreover, for these categories
of patients, a triple therapy (ICS + LABA + LAMA) is
recommended as an alternative.
It is necessary to mention that the overlap syndrome is
considered to be one of the four COPD clinical phenotypes,
according to the Spanish Guideline for Treatment of stable
COPD [16] (Gula Espanola de la EPOC - GesEPOC). The
term Asthma-COPD overlap syndrome (ACOS) was
recognized and for the first time included in GOLD in 2014
[2], but without clear definition and therapeutic options.
Patients with overlap syndrome, “asthmatic smokers”,
present a greater degree of bronchial eosinophilic
inflammation [68, 69]. That is why they have a good
response to inhaled corticosteroids, even early in the course
of disease (mild and moderate COPD). Consequently,
patients with overlap syndrome should be started on inhaled
corticosteroids together with long-acting bronchodilators
irrespective of the severity of the airflow obstruction, in
contrast to previous guidance [70, 71]. In severe cases
LAMA can be added as well [70, 72].
CONCLUSION
COPD is a heterogeneous and complex disease. The
management of COPD in every patient should be
personalized and guided by the symptoms, exacerbations,
pulmonary function and co-morbidities. Unfortunately very
few treatments can slow the rate of lung function decline or
significantly reduce mortality, therefore prevention of the
disease is very important.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict
of interest.
ACKNOWLEDGEMENTS
Declared none.
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Table 2. Comparison of GOLD and Spanish Guideline for Treatment of stable COPD for COPD Management
GOLD Staging
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NON-EXACERBATOR
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Received: February 6, 2014 Revised: February 18, 2014 Accepted: February 20, 2014