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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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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

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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-

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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].

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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

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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 GOLD 1st Line Phenotypes Spanish Guidelines 1st Line

NON-EXACERBATOR (1 exacerbation not leading to

hospital admission)

A B

SABA or SAMA LAMA or LABA

non-exacerbator, with emphysema or chronic

bronchitis

LAMA or LABA SABA or SAMA

EXACERBATOR (≥ 2 exacerbations or ≥ 1

exacerbation leading to hospital admission)

C D

ICS+LABA or LAMA ICS+LABA and/or

LAMA

exacerbator with emphysema exacerbator with chronic

bronchitis

LAMA or LABA LAMA or LABA

Asthma COPD overlap syndrome (ACOS)

No recommendations in GOLD 2014

mixed COPD-asthma phenotype

LABA+ICS

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Received: February 6, 2014 Revised: February 18, 2014 Accepted: February 20, 2014