Diagnosis and pharmacotherapy of stable chronic obstructive pulmonary disease: the Finnish Guidelines

MiniReview Diagnosis and Pharmacotherapy of Stable Chronic Obstructive Pulmonary Disease: The Finnish Guidelines Hannu Kankaanranta 1,2 , Terttu Harju 3 , Maritta Kilpel€ ainen 4 , Witold Mazur 5 , Juho T. Lehto 6,7 , Milla Katajisto 5 , Timo Peisa 8 , Tuula Meinander 9,10 and Lauri Lehtim€ aki 2,11 1 Department of Respiratory Medicine, Sein€ ajoki Central Hospital, Sein€ ajoki, Finland, 2 Department of Respiratory Medicine, University of Tampere, Tampere, Finland, 3 Department of Internal Medicine, Unit of Respiratory Medicine, Medical Research Center, Oulu University Hospital, Oulu, Finland, 4 Department of Respiratory Medicine, University of Turku, Turku, Finland, 5 Heart and Lung Center, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland, 6 Department of Palliative Medicine, University of Tampere, Tampere, Finland, 7 Department of Oncology, Tampere University Hospital, Tampere, Finland, 8 Ranua Health Care Center, Ranua, Finland, 9 Finnish Medical Society Duodecim, Helsinki, Finland, 10 Department of Internal Medicine, Tampere University Hospital, Tampere, Finland and 11 Allergy Centre, Tampere University Hospital, Tampere, Finland (Received 29 September 2014; Accepted 7 December 2014) Abstract: The Finnish Medical Society Duodecim initiated and managed the update of the Finnish national guideline for chronic obstructive pulmonary disease (COPD). The Finnish COPD guideline was revised to acknowledge the progress in diagnosis and management of COPD. This Finnish COPD guideline in English language is a part of the original guideline and focuses on the diagnosis, assessment and pharmacotherapy of stable COPD. It is intended to be used mainly in primary health care but not forgetting respiratory specialists and other healthcare workers. The new recommendations and statements are based on the best evidence available from the medical literature, other published national guidelines and the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. This guideline introduces the diagnostic approach, differential diagnostics towards asthma, assessment and treatment strategy to control symptoms and to prevent exacerbations. The pharmacotherapy is based on the symptoms and a clinical phenotype of the individual patient. The guideline defines three clinically relevant phenotypes including the low and high exacerbation risk phenotypes and the neglected asthma–COPD overlap syndrome (ACOS). These clinical phenotypes can help clinicians to identify patients that respond to specific pharmacological interventions. For the low exacerbation risk phenotype, pharmacotherapy with short-acting b 2 -agonists (salbutamol, terbutaline) or anticholinergics (ipratropium) or their combination (fenoterol–ipratropium) is recommended in patients with less symptoms. If short-acting bronchodilators are not enough to control symptoms, a long-acting b 2 -agonist (formoterol, indacaterol, olodaterol or salmeterol) or a long-acting anticholinergic (muscarinic receptor antagonists; aclidinium, glycopyrronium, tiotropium, umeclidinium) or their combination is recommended. For the high exacerbation risk phenotype, pharmacotherapy with a long-acting anticholinergic or a fixed combination of an inhaled glucocorticoid and a long-acting b 2 -agonist (budesonide–formoterol, beclomethasone dipropionate–formoterol, fluticasone propionate–salmeterol or fluticasone furoate–vilanterol) is recommended as a first choice. Other treatment options for this phenotype include combination of long-acting bronchodilators given from separate inhalers or as a fixed combination (glycopyrronium–indacaterol or umeclidinium–vilanterol) or a triple combination of an inhaled glucocorticoid, a long-acting b 2 -agonist and a long-acting anticholinergic. If the patient has severe-to-very severe COPD (FEV 1 <50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators, the pharmacotherapy may include also roflumilast. ACOS is a phenotype of COPD in which there are features that comply with both asthma and COPD. Patients belonging to this phenotype have usually been excluded from studies evaluating the effects of drugs both in asthma and in COPD. Thus, evidence-based recommendation of treatment cannot be given. The treatment should cover both diseases. Generally, the therapy should include at least inhaled glucocorticoids (beclomethasone dipropionate, budesonide, ciclesonide, fluticasone furoate, fluticasone propionate or mometasone) combined with a long-acting bronchodilator (b 2 -agonist or anticholinergic or both). The Finnish Medical Society Duodecim has created a system for the production of national guidelines on the most important diseases. These guidelines provide the basis of evidencebased treatment of about 100 common health problems and are based on a rigorous evaluation of evidence and production of the guidelines in a specific format including formal level of evidence statements (A–D; see table 1) [1], and this level of evidence is also referred in the current MiniReview. The major difference between the current guideline and most other guidelines for chronic obstructive pulmonary disease (COPD) is that the short reviews of the literature presenting the evidence supporting the claim for a certain level of evidence (A–D) are publicly available [1,2]. These guidelines and statements (in the Finnish language) are published on the website of the medical society Duodecim [1,2] and are available to all physicians as well as to the general public in Finland. In addition, patient versions are occasionally published. During summer 2012, the Finnish Medical Society Duodecim and the Finnish Author for correspondence: Hannu Kankaanranta, Department of Respiratory Medicine, Sein€ ajoki Central Hospital, 60220 Sein€ ajoki, Finland (fax +358 6 415 4989, e-mail [email protected]). ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. Basic & Clinical Pharmacology & Toxicology, 2015, 116, 291–307 Doi: 10.1111/bcpt.12366 Respiratory Society invited members to a group aiming to update the previous guideline on COPD. The production of the novel guideline was started in October 2012, and the final version of the guideline (in Finnish) was accepted and published on 13 June 2014 after a long review process [2]. In Finland, the diagnostics and treatment of common respiratory diseases such as asthma and COPD are mainly performed in primary health care by general practitioners, and only a part of the patients are treated by respiratory specialists. The Finnish Medical Society Duodecim represents the whole medical community in Finland, and the society necessitates that the guideline should serve especially the general practitioners working in primary health care. However, the guideline is also widely used by respiratory specialists and other healthcare specialists such as nurses and pharmacists. Thus, the main requirements for the guideline were that it should be evidence based, accurate, clear and simple enough to be used in a busy general practice. The need to update the guideline for the treatment of COPD was aroused by the prevalence of COPD in the Finnish patients and its importance and costs to patients and to the healthcare system as well as the paradigm shift in the treatment of COPD started by the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report [3]. This guideline greatly owes to the international GOLD report [3] as well as to the innovative guideline for COPD by the Spanish Respiratory Society [4]. The present guideline introduces a modified and hopefully, simplified version of pharmacological treatment based on the assessment of exacerbation risk presented in the GOLD report [3] and Spanish guideline [4]. It takes into the account the neglected phenotype of COPD–asthma as presented in the Spanish COPD guideline [4,5] or asthma–COPD overlap syndrome (ACOS) as termed by the recent GINA report [6]. Asthma and COPD are generally diagnosed, treated and managed by the same personnel (nurses and general practitioners) in Finland. As there are some crucial differences in the treatment of these two common diseases, accurate diagnosis and clear treatment guidelines are of utmost importance. Thus, in the preparation of the present guideline, the diagnostic section was co-ordinated with the recently published asthma guideline as three members served in this group (H.K., T.H. and L.L.) who were also involved in the production of the asthma guideline [7]. Special attention was drawn to the diagnosis of COPD, differential diagnosis between asthma and COPD, and the inclusion of the ACOS. In addition, the pharmacological treatment section was developed to pursue readiness, simplicity and in-depth precision at the same time. This Finnish COPD guideline in the English language covers only a part of the original guideline [2,8,9], that is the diagnostics, comprehensive assessment and pharmacological treatment of stable COPD. Other sections such as epidemiology, screening, tobacco cessation, oxygen therapy, ventilatory support, surgical treatments, pulmonary rehabilitation, management of acute exacerbations and palliative care can be found in the original document in Finnish [2,9]. This version of the guideline has been updated to contain some novel compounds (e.g. umeclidinium), fixed combinations of long-acting bronchodilators (glycopyrronium–indacaterol and umeclidinium–vilanterol) and fixed combinations of inhaled glucocorticoids (ICS) and longacting b 2 -agonists (beclomethasone dipropionate–formoterol and fluticasone furoate–vilanterol) not included in the earlier published Finnish version [2,8] and now available in Finland. In addition, new relevant literature has been cited. Diagnostics The diagnosis of COPD is based on relevant exposure history, symptoms and airway obstruction that is not fully reversible (post-bronchodilator forced expiratory volume in one-second/ forced vital capacity <0.70; FEV 1 /FVC <0.70). Evaluation of predisposing factors. The following predisposing factors should be assessed in the diagnostic evaluation: smoking history (in pack-years), current smoking, passive smoking, occupational exposures, previous respiratory infections, asthma and respiratory diseases in the family. Symptoms. Typical symptoms of COPD include dyspnoea, chest tightness, wheezing, cough and sputum production [3], but the diagnosis of COPD cannot be based on symptoms alone, as some patients are symptom free and similar symptoms can be caused by other diseases [10]. However, symptoms suggestive of COPD in an individual with exposure to tobacco or other risk factors should lead to spirometry and other diagnostic evaluations. In patients with established COPD, the level of symptoms and the presence of exacerbations should be assessed as these are used to guide the treatment Table 1. Grading of the evidence in the Current Care Guidelines. Level of evidence Description (verbal expression in the text) A Strong research-based evidence (multiple, relevant, high-quality studies with homogeneous results –e.g. two or more randomized, controlled trials or a systematic review with clearly positive results) B Moderate evidence (e.g. one randomized, controlled trial or multiple adequate studies) (...apparently...) C Limited research-based evidence (e.g. controlled, prospective studies) (...may...) D No evidence (e.g. retrospective studies or the consensus reached in the absence of good-quality evidence) Adapted from reference [1]. ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). 292 HANNU KANKAANRANTA ET AL. MiniReview [3]. COPD is a progressive disease and symptoms tend to worsen, especially if the patient continues smoking, and dyspnoea at rest or light exercise, cough, weight loss and frequent exacerbations are often present in advanced severe-tovery severe COPD [11]. Physical examination. The diagnosis of COPD cannot be based on clinical signs, but these can be suggestive of COPD and its degree of severity [3]. Wheezing may be heard during auscultation of the chest, but pulmonary sounds can also be normal. Increased respiratory rate at rest, the use of accessory respiratory muscles and signs of right-sided heart failure may be present in severe COPD. Pulmonary function testing. In diagnosing COPD, spirometry should be conducted with bronchodilation test. COPD can be diagnosed if FEV 1 /FVC is <0.70 in a post-bronchodilation spirometry [3]. This criterion causes some over-diagnosis in elderly people [12,13] and possibly also in women [14] and under diagnosis in individuals younger than 45 years [13], but it is sensitive in detecting COPD clinically assessed by a physician [15–17]. This criterion is also associated with mortality risk [18]. Significant reversibility in the bronchodilation test (FEV 1 increases at least 12% and 200 ml) can be detected in approximately 25–50% of individuals with COPD (see Differential diagnosis below). Classification of severity of airway obstruction is presented in table 2, but this is only one aspect of the clinical severity of COPD. Radiological imaging. The diagnosis of COPD cannot be based on chest X-ray, but a chest X-ray should be included in the initial evaluation to exclude other diseases such as pulmonary cancer, tuberculosis, pneumonia, heart failure and pleural diseases. In mild COPD, chest X-ray is almost always normal. In advanced disease flattening of the diaphragm, long narrow heart, over-inflation with thinning of blood vessels and emphysematous bullae can be seen. Computerized tomography of the chest is not routinely needed, but may be used by specialists in cases of problematic differential diagnosis to detect bronchiectasis and in the evaluation for surgical treatment of COPD [19]. Blood tests and sputum cultures. There are no specific blood tests to be used in diagnosing COPD, but some basic tests may be used to rule out other diseases and to assess infections and respiratory failure during acute exacerbations. Bacterial culture of sputum is not useful in stable COPD. If COPD is found in a person with exceptionally young age (<45 years) or with a low smoking history (<20 pack-years), serum levels of alpha-1-antitrypsin (A1AT) should be measured to rule out alpha-1-antitrypsin deficiency. This recommendation may differ from that of other guidelines [3]. However, screening for A1AT is not recommended for all patients in Finland, because there is no A1AT replacement therapy available in Finland. Thus the only relevant therapeutic option is counselling for smoking cessation and the smoking cessation is recommended for all patients with COPD despite the knowledge of A1AT levels. Comprehensive evaluation of the patient. Symptoms, quality of life and the impact of the disease can be assessed with validated questionnaires such as COPD Assessment Test â (CAT â ) and modified Medical Research Council Dyspnea Scale (mMRC) [3]. Six-minute walking test or ergometry can be used to assess exercise tolerance. The clinical severity of COPD is assessed based on the degree of airway obstruction, level of symptoms, exacerbations and co-morbidities (table 2). Extra-pulmonary manifestations and co-morbidities such as cardiovascular diseases, metabolic syndrome, osteoporosis and depression are more prevalent in individuals with COPD than in non-COPD individuals with Table 2. Classification of the severity of obstruction and the clinical severity of chronic obstructive pulmonary disease (COPD). Severity of obstruction (assessed after bronchodilation) Clinical severity of COPD Mild FEV 1 ≥80% predicted Good quality of life (CAT â <10), no frequent exacerbations and FEV 1 >50% predicted Moderate 50% ≤FEV 1 <80% One of the following: FEV 1 <50% predicted At least two exacerbations a year or one hospitalization because of COPD COPD has a medium impact on life (e.g. CAT â ≥10 points) or causes poor quality of life or impaired exercise tolerance Severe 30% ≤FEV 1 <50% Very severe FEV 1 <30% One of the following: FEV 1 <30% predicted Chronic respiratory failure Frequent exacerbations or hospitalizations regardless of treatment to COPD COPD has a high or very high impact on life (e.g. CAT â ≥20 points) or causes very poor quality of life or exercise tolerance ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). MiniReview FINNISH COPD GUIDELINE 293 similar smoking history. Nutritional status and especially unintended loss of weight should be assessed. Differential diagnosis. The most important differential diagnoses include asthma, chronic bronchitis, lower airway infections (including tuberculosis), lung cancer, interstitial lung diseases and heart diseases. A common diagnostic problem is to distinguish between asthma and COPD. Although these diseases are often treated with the same medication, they differ in basic pathology, aetiology and prognosis. COPD and asthma are often found in the same individual, and in smoking asthma patients, the cellular components of inflammation may resemble that found in COPD [3,6]. The differential diagnosis of asthma and COPD cannot be based on pulmonary function tests alone, but a comprehensive approach including smoking history, symptoms, co-morbidities and family history is needed [3,6]. Bronchodilation test in spirometry cannot reliably distinguish between asthma and COPD [3], as asthmatic individuals do not always present with significant reversibility and approximately 25–50% of individuals with COPD have significant reversibility [20–22]. Glucocorticoid therapy test does not always differentiate between asthma and COPD [23], as a considerable proportion of individuals with COPD benefit from ICS [24]. On the other hand, some of the asthmatic individuals are not responsive to ICS alone [25]. However, if an individual patient clearly benefits from using ICS (i.e. as assessed based on improvement in lung function or based on a reduction of symptoms or exacerbations), it should be continued regardless of the diagnosis (asthma or COPD). As the response to oral glucocorticoids does not predict responsiveness to ICS [26,27], the possible treatment trials should be conducted using ICS at moderate (to high) doses for (4 to) 8 weeks. Normalization of lung function by ICS treatment excludes COPD and strongly supports the diagnosis of asthma. If the lung function is not significantly changed by ICS treatment, the diagnosis is more likely COPD than asthma. Aims of the Treatment of COPD The goals of the therapy of COPD can be divided into four major aims: 1Controlling symptoms and improving the quality of life. 2Reducing future risk, that is preventing exacerbations. 3Slowing down the progression of the disease. 4Reducing mortality. Multimodal Therapy of COPD The therapy of COPD includes both non-pharmacological and pharmacological means. Non-pharmacological treatment modalities include smoking cessation [28], oxygen therapy, physical exercise and pulmonary rehabilitation, ventilator support and surgical therapy. Palliative care in patients nearing death is discussed in detail in the original document and may include a trial of opioids for refractory dyspnoea [2,9]. The risk of physical inactivity in patients with COPD is vastly increased (A) [29], and the patients should be encouraged to do physical exercise. Physical activity reduces the risk of mortality and hospitalizations. In contrast, physical inactivity predicts increased mortality (A) [30,31]. Exercise-based pulmonary rehabilitation courses should be available for COPD patients with continued dyspnoea despite the use of bronchodilators, or when they are physically inactive and suffer from frequent exacerbations, or have exercise intolerance. These recommendations can be found in detail in the original document [2,8,9]. Pharmacological therapies include bronchodilators, combinations of ICS and long-acting bronchodilators, phosphodiesterase 4 (PDE4) inhibitors or theophylline and influenza and pneumococcal vaccination. Vaccination In the general population, vaccination of persons aged >65 years against influenza has been found to reduce pneumonia, hospitalization and deaths by 50–68%. A majority of patients with COPD belong to this age group. Vaccination against influenza reduces COPD exacerbations (A) [32]. Vaccination annually against influenza is recommended for all patients with COPD. Pneumococcal vaccination apparently reduces pneumonia of pneumococcal origin in patients with COPD (B) [33–35]. Pneumococcal vaccination is recommended for patients with COPD. Pharmacotherapy of Stable COPD Principles of regular long-term pharmacotherapy of COPD. 1There exist two main goals with the current pharmacotherapy of COPD. They are (1) to control symptoms and (2) to reduce future risk (i.e. the exacerbations of COPD). The grounds for the use of any particular treatment in COPD may be either one of these goals or both goals together. The continuation or termination of a specific therapy is decided based on which goal is targeted (fig. 1). 2If a particular pharmacotherapy is started in an effort to achieve both goals, the decision whether to continue or discontinue is made based on goal 2, that is the aim to reduce future risk (exacerbations). This is because the ability or inability of any particular drug to improve lung function or symptoms is not known to predict its ability to reduce exacerbations of COPD. 3The pharmacological groups of inhaled drugs and the compounds used in the pharmacotherapy of COPD are shown in table 3. 4The effects of several pharmacotherapies of COPD as well as the effects of smoking cessation and exercise on different end-points and goals in the treatment of COPD are shown in table 4. 5The pharmacotherapy of COPD is based on the individual patient phenotype, on the level of symptoms and the risk of exacerbations. These are described in the section ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). 294 HANNU KANKAANRANTA ET AL. MiniReview ‘COPD phenotypes and phenotype-specific pharmacotherapy of COPD’. Grouping of patients to three different phenotypes is shown in fig. 2. 6Phenotype and phenotype-based pharmacotherapy (fig. 2) should be evaluated at every visit to health care as the phenotype may change when the disease progresses (especially with regard to an increase in exacerbation risk) [36]. 7So far, no pharmacotherapy has definitively been shown to slow down disease progression (annual FEV 1 decline) or reduce mortality [37–43], even though preliminary findings suggesting such effects have been published. 8The principles for combining different drugs in the treatment of COPD are shown in table 5. 9A short-acting bronchodilator to be used on as-needed basis is considered beneficial for most patients treated with long-acting bronchodilators or combination therapy including long-acting bronchodilators. Bronchodilators. Drugs that relieve bronchial obstruction by reducing bronchial smooth muscle contraction are called bronchodilators. Usually, they improve spirometric values reflecting obstruction such as FEV 1 . These compounds generally improve also emptying of the lungs and reduce air trapping (dynamic hyperinflation/ restriction) both at rest and during exercise [44]. These effects cannot be predicted based on the ability of the particular compound to improve FEV 1 [45–48]. The dose–response effect of all bronchodilators at the currently used doses is relatively flat, which means that a small increase (e.g. doubling) in the dose is not expected to produce a vast increase in the bronchodilatory action [49–51]. The adverse effects are generally dose-related. Increase in the dose of short-acting inhaled b 2 -agonist and anticholinergic, especially when given nebulized, may relieve subjective dyspnoea in acute setting during an exacerbation of COPD but may not help as a long-term therapy [52,53]. Bronchodilators can be divided into short acting (duration of bronchodilatory effect generally 3–6 hr) and long acting (duration of bronchodilatory effect generally 12–24 hr). There are two different classes of bronchodilators that have basically similar bronchodilatory action in the treatment of COPD but different mechanism of action. These pharmacological classes are b 2 -agonists and muscarinic receptor (M 1 ,M 2 and M 3 ) antagonists (termed anticholinergics) [54,55]. Both of these pharmacological classes contain short-acting and long-acting preparations. Bronchodilators are usually administered on either as-needed (usually short-acting preparations) or regularly (usually long-acting preparations) to treat or prevent the occurrence of symptoms. A short-acting bronchodilator to be used as-needed is considered beneficial for most patients even though they were treated with long-acting bronchodilators or combination therapy including long-acting bronchodilators. Instead, the use of regular, high-dose (nebulized, etc.), short-acting bronchodilator or their combination in patients treated with long-acting bronchodilators is not evidence based [3] and should only be reserved to treatment of the most difficult cases. In such a situation, the need for long-acting bronchodilators should be carefully evaluated as well as the ability of the patient to properly inhale them. Shortand long-acting b 2 -agonists (SABA, LABA). The main beneficial effect of b 2 -agonists is the reduction of bronchial smooth muscle contraction that leads to relief of bronchial obstruction. The duration of the effect of short-acting b 2 -agonists is usually 3–6 hr. Short-acting b 2 -agonist used either as-needed or regularly reduce symptoms of COPD and improve lung function [56]. The effect of long-acting b 2 - Long-term pharmacological treatment of COPD has two separate aims, but same medication may help in achieving therapeutic benefit in both aims. Aim 1: Controlling symptoms Bronchodilation; reduction of symptoms either short-term or long-term • SABA: fenoterol, salbutamol, terbutaline • SAMA: ipratropium • LABA: formoterol, indacaterol, olodaterol, salmeterol • LAMA: aclidinium, glycopyrronium, tiotropium, umeclidinium • Teophylline (?) Aim 2: Reducing future risk Preventing future exacerbations of COPD • LAMA: Tiotropium, aclidinium, glycopyrronium, umeclidinium • ICS + LABA • LABA: salmeterol, formoterol, olodaterol, indacaterol • LABA + LAMA • Roflumilast How to evaluate the effectiveness of the medication and how to decide whether to stop or continue medication? Evaluate first whether the given medication is used to achieve aim 1 or aim 2. If the given drug is used to achieve both aims, the decision whether or not to continue is made based on the criteria shown for the aim 2. Aim 1: One or more of the following findings in the absence of severe adverse events support the continuation of the given medication • Reduction in daily symptoms • symptom assessment e.g. by CAT®-test • Improvement in exercise tolerance • Improvement in objective lung function measurements (e.g. FEV1, FVC or PEF; however, this is not a prerequisite to continue medication) Aim 2: One or more of the following findings supports stopping the medication: • Appearance of a severe adverse effect • Appearance of a mild to moderate adverse effect that is frequent and/or affects the quality of life (e.g. repeating episodes of candidiasis or diarrhoea) and disappears after stopping the medication • Of note! Lack of improvement in symptoms or lung function is not a reason to stop medication! Fig. 1. Aims of the pharmacotherapy of chronic obstructive pulmonary disease (COPD) and principles for the evaluation whether to continue or discontinue the current medication. ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). MiniReview FINNISH COPD GUIDELINE 295 agonists lasts 12 hr (formoterol or salmeterol) or 24 hr (indacaterol, olodaterol or vilanterol). The bronchodilatory action of formoterol/indacaterol/olodaterol/vilanterol starts sooner (within 5 min.) than that of salmeterol (within 20–30 min.). Indacaterol improves lung function (e.g. FEV 1 ), reduces dyspnoea during exercise and improves the quality of life, but the evidence on the reduction of COPD exacerbations is still preliminary [57–60]. The efficacy of indacaterol, olodaterol or vilanterol, when measured using FEV 1 or quality of life, is at least as good as that of formoterol or salmeterol [58,61–63] or the long-acting anticholinergic tiotropium [58,61,64]. Generally, b 2 -agonists are well tolerated. Typical adverse effects include tremor, tachycardia and palpitations that have been reported in <1% of patients. Headache, muscular cramps and an increase in the blood glucose and a decrease in potassium levels are possible, even though these events occur almost as often in patients treated with placebo [65]. It has been suggested that activation of heart b 2 -receptors by b 2 -agonists might induce ischaemia, cardiac insufficiency and arrhythmias or increase the risk of sudden death. However, in controlled clinical studies recruiting patients with COPD, there is no indication for the increase of arrhythmias or cardiac deaths [65] or overall mortality [66] by b 2 -agonists. Based on a case–control study [67], an increase in the risk of severe arrhythmias is possible. Thus, the benefits of using long-acting b 2 -agonist in patients with severe cardiac disease should be carefully considered. The use of long-acting b 2 -agonists in the treatment of asthma in the absence of simultaneous ICS is prohibited [7] because there is evidence that treatment of asthma with longacting b 2 -agonists in the absence of ICS increases mortality due to asthma [68]. In contrast, in the treatment of COPD, a long-acting b 2 -agonist can be used as the sole therapy as it does not increase mortality in COPD according to the studies published [65,66]. According to some cohort studies, use of long-acting b 2 -agonist may even reduce the mortality of patients with COPD [69,70]. Shortand long-acting anticholinergics (SAMA, LAMA). Anticholinergic compounds block muscarinic receptors (M 1 ,M 2 and M 3 ), thus antagonizing acetylcholine-induced bronchial smooth muscle contraction. The duration of the effect of short-acting anticholinergic (ipratropium) is usually somewhat longer (even up to 8 hr) than that of the short-acting b 2 -agonists (3–6 hr), but starts more slowly [54,55]. The effect of long-acting anticholinergics lasts either 12 hr (aclidinium) or approximately 24 hr (glycopyrronium, tiotropium or umeclidinium). Of these, tiotropium has been most extensively studied and used. The bronchodilatory action of aclidinium and glycopyrronium starts sooner than that of tiotropium. Tiotropium improves lung function and quality of life and reduces symptoms and exacerbations of COPD (A) [71]. In contrast, tiotropium does not affect the progression of the disease as judged by the annual decline in FEV 1 [72]. Tiotropium may be more effective than salmeterol in reducing exacerbations of COPD [73]. Both aclidinium and glycopyrronium have been shown to induce bronchodilation, improve lung function and quality of life and reduce the need for rescue medication [74,75], and their efficacy roughly equals to that of tiotropium. Aclidinium, glycopyrronium and umeclidinium have been shown to reduce COPD exacerbations in studies lasting up to 1 year [76–78], but long-term studies lasting more than 1 year, similar to those made with tiotropium [72,73], are still lacking. Inhaled anticholinergics are generally well tolerated, and adverse effects occur relatively seldom. Typical adverse effects, such as dry mouth, blurred vision, throat irritation, rhinitis, constipation and nausea, are due to blocking of muscarinic receptors. Other possible adverse effects include also arrhythmias, urinary retention/obstruction, elevated intraocular pressure and acute or worsening of narrow-angle glaucoma [79]. The short-acting anticholinergic ipratropium has been suspected to induce cardiac adverse effects [79]. With the longacting anticholinergics, no similar increase in cardiac adverse effects has been reported with certainty [79]. The 4-year-long UPLIFT trial reported that there were statistically significantly less cardiac adverse effects and the total mortality was numerically, although not statistically, lower in patients treated with tiotropium [72]. Recently, it has been proposed that dosing of tiotropium with Respimat â device (Boehringer Ingelheim, Ingelheim, Table 3. Pharmacological compounds used in the therapy of chronic obstructive pulmonary disease. Pharmacological group and its abbreviation Compounds belonging to the group Short-acting b 2 -agonists Salbutamol Terbutaline Long-acting b 2 -agonist (LABA) Formoterol Indacaterol Olodaterol Salmeterol Vilanterol Short-acting anticholinergic Ipratropium Long-acting anticholinergic (LAMA) Aclidinium Glycopyrronium Tiotropium Umeclidinium Inhaled glucocorticoids (ICS) Beclomethasone dipropionate Budesonide Ciclesonide Fluticasone propionate Fluticasone furoate Mometasone Fixed combination of inhaled glucocorticoid and long-acting b 2 -agonist (ICS +LABA) Budesonide–formoterol Beclomethasone dipropionate– formoterol Fluticasone propionate–salmeterol Fluticasone furoate–vilanterol Fixed combination of long-acting anticholinergic and long-acting b 2 -agonist (LAMA +LABA) Glycopyrronium–indacaterol Umeclidinium–vilanterol Phosphodiesterase 4 (PDE4) inhibitors Roflumilast Others Theophylline ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). 296 HANNU KANKAANRANTA ET AL. MiniReview Table 4. Effects of smoking cessation, exercise and various pharmacotherapies in the treatment of chronic obstructive pulmonary disease (COPD). Smoking cessation Exercise Short-acting bronchodilator (b 2 -agonist or anticholinergic) Long-acting b 2 -agonist Long-acting anticholinergic Addition of inhaled glucocorticoid in severe COPD 1 Roflumilast in severe COPD Symptoms ++ + + + (+) Obstruction ++++ (+)(+) Exacerbations ++ ++ + + Disease progression (annual FEV 1 decline) +? (+)? Mortality ++  (+)? +: definite beneficial effect; (+): small or possible beneficial effect; : no effect; ?: no evidence. 1 In practice means terminating long-acting b 2 -agonist and prescribing a combination product containing both inhaled glucocorticoid and long-acting b 2 -agonist. Is it asthma-COPD overlap? Low exacerbation risk Asthma-COPD overlap syndrome (ACOS) High exacerbation risk When should COPD be suspected? • Post-bronchodilataon FEV1/FVC < 0.7 in spirometry • Risk factors: smoking history > 10 pack-years (somemes long-term heavy exposure to dust or alpha-1antrypsin deficiency) • Symptoms typical to COPD: cough, sputum producon, dyspnoea (in exercise), wheezing – Of note: some of the paents are asymptomac Is it un-treated asthma? • If obstrucon can be totally reversed (FEV1/FVC ≥ 0.7) with treatment (inhaled glucocorcoid, long-acng β2-agonist can be added) is not COPD • Consider whether the criteria for asthma is met Diagnose COPD if • Despite possible therapy, obstrucon (post-bronchodilator FEV1/FVC < 0.7) remains • There is idenfiable risk-factor for COPD (smoking > 10 pack-years, heavy long-term dust exposure or alpha-1-antrypsin deficiency) • Disease presentaon conforms COPD (e.g. not untreated asthma) • The paent may have both COPD and asthma (see below) Treatment for all paents with COPD • Smoking cessaon • Frequent exercise (consider special pulmonary rehabilitaon) • Vaccinaon: influenza (yearly), pneumococcal Phenotypespecific therapy • Is it asthma-COPD overlap syndrome (ACOS)? • What is the exacerbaon risk? Has there been ≥ 2 COPD exacerbations or one leading to hospitalization during last year or is FEV1< 50 % predicted ? see criteria Drug therapy is a combination from COPD and asthma guidelines Notice both diseases! Generally, medication includes at least the following •ICS + LABA or •ICS + LABA + LAMA Try these, combination possible Consider risks and benefits individually •LAMA •ICS + LABA •LAMA + LABA •Roflumilast (if frequent exacerbations, chronic bronchitis and FEV1< 50 % predicted) Less symptoms (CAT®score <10) •SABA and/or SAMA as needed More symptoms (CAT®score ≥10) •Daily LABA and/or LAMA •Consider alternative diagnosis, especially cardiac disease •(Theophylline) Criteria for asthma-COPD overlap syndrome 2 main criteria, or 1 main and 2 additional criteria Main criteria • Significant bronchodilatory response (FEV1> 15 % and > 400 ml) • Sputum eosinophilia or elevated (>50 ppb) exhaled NO • Previous asthma symptoms (starting age at < 40 y) Additional criteria • Elevated total IgE • Atopy • Repeated significant bronchodilatory response (FEV1> 12 % and > 200 ml) • PEF-follow-up typical to asthma Consider referral to respiratory specialisf • There are diagnosc problems • There are therapeuc problems • The ability to work is in queson • Long-term oxygen therapy is considered (SaO2< 90 % at rest and stopped smoking) Fig. 2. The principles of diagnostics and phenotype-specific therapy of chronic obstructive pulmonary disease (COPD). Of note, the current indication for the use of different fixed combinations of inhaled glucocorticoid ICS and long-acting b 2 -agonist (LABA) in COPD is frequent exacerbations despite the use of appropriate bronchodilator therapy, but the FEV 1 ranges from <50% predicted (budesonide–formoterol, beclomethasone dipropionate–formoterol) to <60% predicted (fluticasone propionate–salmeterol) and to <70% predicted (fluticasone furoate–vilanterol). ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). MiniReview FINNISH COPD GUIDELINE 297 Germany) would cause more deaths than its dosing with Handihaler â device (Boehringer Ingelheim, Ingelheim, Germany) [79]. However, a direct comparison of the two devices for a mean of 2.3 years indicated that there were no differences in mortality, serious cardiac adverse effects or exacerbations of COPD [80]. Combination bronchodilator therapy. Bronchodilators with a different mechanism or duration of action can be relatively freely combined (table 5), and the combination may have a better bronchodilatory effect [81]. For example, combination of a short-acting anticholinergic with a shortor long-acting b 2 -agonist improves FEV 1 better than any of the single agents [81,82]. Shortor long-acting b 2 - agonist can be combined with a long-acting anticholinergic if a single agent is not improving symptoms enough [81–83]. The combination of tiotropium and a long-acting b 2 -agonist apparently improves the lung function and quality of life somewhat better than tiotropium alone (B) [83]. The use of shortand long-acting anticholinergic compounds together is not recommended. Even though this combination may improve results of lung function tests better than the single agents, it will increase the risk of adverse effects such as urinary retention [84]. Combination of a short-acting b 2 -agonist with a long-acting anticholinergic will result in at least as good a response in lung function parameters without a risk of anticholinergic adverse effects. Thus, if a patient is using a long-acting anticholinergic, the rescue medication should be a shortacting b 2 -agonist [84]. After the finalization of the Finnish guideline [2,8,9], two fixed-dose combinations of a long-acting b 2 -agonist and a long-acting anticholinergic have been approved to be used in the treatment of COPD, namely indacaterol–glycopyrronium and vilanterol–umeclidinium. In most studies, both of these fixed combinations have been shown to improve lung function (e.g. trough FEV 1 ) and health status and to reduce dyspnoea better than the single monocomponents alone in patients with moderate-to-severe COPD with no apparent safety concerns [64,85–89]. In addition, the fixed-dose combination of indacaterol–glycopyrronium has been reported to reduce moderateto-severe COPD exacerbations better than glycopyrronium alone [90]. Inhaled glucocorticoids. In the treatment of asthma, the therapeutic and adverse effects of ICS depend on the dose used [91]. Instead, in the treatment of COPD, the dose dependency of the therapeutic and adverse effects of ICS is not known [92,93]. In long-term trials, only moderate and high doses of ICS have been used [92,93]. Regular long-term (>6 months) therapy with ICS in COPD reduces exacerbations and slows down the decline in the quality of life [93]. Generally, patients with mild disease and without previous exacerbation history do not benefit from ICS [3,93]. The response to ICS in COPD cannot be foretold from the response to oral glucocorticoids or by measuring hyperreactivity or response to bronchodilators (bronchodilator test in spirometry) [93]. Discontinuation of ICS may precipitate exacerbation of the disease in some patients with COPD [94] but may be safely performed in others to decrease risk of long-term adverse effects [95]. ICS alone do not affect mortality due to COPD or the rate of decline of lung function (annual FEV 1 decline) [93]. Adverse effects include candida infection in the mouth and hoarseness. Also, there is evidence that use of ICS is associated with an increased risk of pneumonia [93] and fractures [96]. Initiation of ICS therapy has been associated with increased risk of diabetes in respiratory Table 5. The principles of combining drugs used to treat chronic obstructive pulmonary disease (COPD). The general rule of drug therapy of COPD is that two drugs belonging to the same group or having similar mechanism of action should not be combined. The exception to this rule is the simultaneous use of shortand long-acting b 2 -agonists that is allowed and often is meaningful. If there is a clinical indication to combine drugs from the following groups, there is no pharmacological reason to prevent the combination. To a single patient, only one compound or product can be selected from the following groups of drugs Short-acting bronchodilators (‘reliever medication’) 1 Short-acting b 2 -agonist (fenoterol, salbutamol, terbutaline) Short-acting anticholinergic (ipratropium) 2 Long-acting bronchodilators 1 Long-acting b 2 -agonist (formoterol, indacaterol, olodaterol, salmeterol, vilanterol) Long-acting anticholinergic (aclidinium, glycopyrronium, tiotropium, umeclidinium) 2 Glucocorticoids Inhaled glucocorticoids (beclomethasone, budesonide, fluticasone, mometasone, ciclesonide) Oral medications Phosphodiesterase 4 inhibitors (roflumilast) 3 Theophylline 3 1 The duration of action of the compound does not prevent the combination. For example, two long-acting bronchodilators can be combined as long as they have a different mechanism of action (i.e. tiotropium and indacaterol can be combined). Similarly, short-acting anticholinergic (ipratropium) can be combined with short-acting b 2 -agonist (e.g. salbutamol). Instead, two different b 2 -agonists with similar duration of action should not be combined (e.g. indacaterol should not be combined with formoterol or salmeterol). Use of a short-acting b 2 -agonist as needed with a regular longacting b 2 -agonist is acceptable. 2 Use of short-acting anticholinergic (ipratropium) with long-acting anticholinergic is not recommended. 3 Phosphodiesterase 4 inhibitors and theophylline should not be combined because of the risk of adverse effects. ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). 298 HANNU KANKAANRANTA ET AL. MiniReview patients in general in a registry-based study [97], but in a retrospective analysis of shorter placebo-controlled, double-blind studies in patients with asthma or COPD, it has not been confirmed [98]. Long-term therapy with ICS in addition to other therapy is recommended only for patients with ACOS or patients with a high risk of exacerbations of COPD, that is with severe or very severe obstruction in spirometry (table 2) and a history of frequent exacerbations (fig. 2) [99]. The use of ICS as the sole long-term therapy of COPD should be avoided as the combination of inhaled glucocorticoid with long-acting b 2 - agonist is more efficient in reducing exacerbations of the disease and possibly better in reducing mortality and improving lung function and quality of life [100]. The use of ICS outside the current indications is not recommended as long-term therapy with these may increase the risk of pneumonia [92,93], osteoporosis and fractures [96]. Combination of inhaled glucocorticoid and long-acting b 2 -agonist. In COPD, the current indication for the use of different fixed combinations of ICS and long-acting b 2 -agonist is frequent exacerbations despite the use of appropriate bronchodilator therapy, but the accepted FEV 1 ranges from <50% predicted (budesonide–formoterol, beclomethasone dipropionate–formoterol) to <60% predicted (fluticasone propionate–salmeterol) and to <70% predicted (fluticasone furoate–vilanterol). The combination of inhaled glucocorticoid and a long-acting b 2 - agonist reduces exacerbations and improves lung function and quality of life in COPD (A) [101]. In addition, combination of inhaled glucocorticoid and a long-acting b 2 -agonist is better than placebo or any of its components in improving lung function and health status and reducing exacerbations in patients with COPD [100,102–105]. In a large, prospective 3-year trial with a combination of inhaled glucocorticoid and a long-acting b 2 -agonist, there was no statistically significant effect on mortality [106]. However, in a subsequent meta-analysis, it was found that a combination of inhaled glucocorticoid and a long-acting b 2 -agonist may reduce mortality (number needed to treat NNT =36 to prevent one extra death; 95% CI 21; 258) [104]. The use of a combination of an inhaled glucocorticoid and a long-acting b 2 -agonist is associated with adverse effects typical for both its components. The increased risk of pneumonia is considered as the most significant in patients with COPD [99,104]. At present, it remains uncertain to what extent increased risk of pneumonia is associated with other ICS or combinations of ICS and long-acting b 2 -agonists, but a combination of inhaled fluticasone propionate and salmeterol may cause a higher risk [107–110]. Even though COPD is largely an under-diagnosed and under-treated disease [3], over-treatment of mild-to-moderate COPD (spirometric GOLD classification; table 2) with combinations of ICS and long-acting b 2 -agonists was recently reported [111]. This cannot be recommended and leads to unnecessary adverse effects and costs [111]. Addition of a combination of an inhaled glucocorticoid and a long-acting b 2 -agonist to tiotropium therapy has been reported to improve lung function and the quality of life, and it may even further reduce the occurrence of exacerbations, particularly severe exacerbations [112–115], but more and longer studies are needed. Preliminary evidence suggests that the triple therapy is cost-effective in Finland and other Scandinavian countries [116]. Roflumilast. Roflumilast inhibits the inflammatory reaction associated with COPD by inhibiting enzyme phosphodiesterase 4 (PDE4) and by increasing intracellular cyclic adenosine monophosphate (cAMP) content [57]. Roflumilast is given orally as one tablet daily. It is not a bronchodilator and cannot be used to relieve acute bronchial obstruction, even though during long-term therapy in patients already on salmeterol or tiotropium, roflumilast further increases FEV 1 by 50–80 ml [57,117–119]. Roflumilast reduces exacerbations of COPD and improves lung function, but it also has significant adverse effects (A) [117]. Roflumilast reduces moderate (requiring systemic glucocorticoids) and severe (leading to hospitalization or death) exacerbations in patients with COPD who have severe COPD (FEV 1 <50% predicted), chronic bronchitis and frequent exacerbations despite long-acting bronchodilators [57,117,118]. In contrast, the effects on the quality of life and symptoms are less pronounced [57,117]. Typical adverse effects of roflumilast are gastrointestinal complaints and headache. Weight loss is also common, and the weight should be followed [117,118]. Other pharmacological treatments used for long-term therapy. Oral glucocorticoids. A treatment trial with oral glucocorticoids is not recommended in patients with COPD to identify those who will respond to ICS. A response to oral glucocorticoids has not been shown to predict the response to other treatments [23–27]. However, this does not prevent us from treating exacerbations with a course of oral steroids or trying a course of oral steroids in a patient with difficult symptoms. Even though a high dose (equalling ≥30 mg oral prednisolone per day) of oral glucocorticoids improves lung function in the short run, there is no evidence of long-term benefits of oral glucocorticoids at low or moderate to high doses [120]. In contrast, there is evidence to suggest increased risk of adverse effects [120]. Thus, long-term therapy of COPD with oral glucocorticoids should be avoided as it may even worsen the long-term outcome of the patient [121]. Oral glucocorticoids have several significant adverse effects –one of the most important in the treatment of COPD being steroid myopathy which presents with symptoms such as muscular weakness, impaired physical activity and respiratory insufficiency in patients with very severe COPD [122]. Regular long-term oral glucocorticoid therapy has several well-known adverse effects, and thus, it is easy to understand that there exist no studies on its use in the treatment of stable COPD [3]. ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). MiniReview FINNISH COPD GUIDELINE 299 105 Wedzicha JA, Singh D, Vestbo J, Paggiaro PL, Jones PW, Bonnet-Gonod F et al. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. 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Respiration 2013;85:160–74. ©2014 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). MiniReview FINNISH COPD GUIDELINE 307