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

MiniRe iew Diagnosis and Pha maco he apy o S able Ch onic Obs uc i e Pulmona y Disease: The Finnish Guidelines Hannu Kankaan an a 1,2 , Te u Ha ju 3 , Ma i a Kilpel€ ainen 4 , Wi old Mazu 5 , Juho T. Leh o 6,7 , Milla Ka ajis o 5 , Timo Peisa 8 , Tuula Meinande 9,10 and Lau i Leh im€ aki 2,11 1 Depa men o Respi a o y Medicine, Sein€ ajoki Cen al Hospi al, Sein€ ajoki, Finland, 2 Depa men o Respi a o y Medicine, Uni e si y o Tampe e, Tampe e, Finland, 3 Depa men o In e nal Medicine, Uni o Respi a o y Medicine, Medical Resea ch Cen e , Oulu Uni e si y Hospi al, Oulu, Finland, 4 Depa men o Respi a o y Medicine, Uni e si y o Tu ku, Tu ku, Finland, 5 Hea and Lung Cen e , Uni e si y o Helsinki and Helsinki Uni e si y Cen al Hospi al, Helsinki, Finland, 6 Depa men o Pallia i e Medicine, Uni e si y o Tampe e, Tampe e, Finland, 7 Depa men o Oncology, Tampe e Uni e si y Hospi al, Tampe e, Finland, 8 Ranua Heal h Ca e Cen e , Ranua, Finland, 9 Finnish Medical Socie y Duodecim, Helsinki, Finland, 10 Depa men o In e nal Medicine, Tampe e Uni e si y Hospi al, Tampe e, Finland and 11 Alle gy Cen e, Tampe e Uni e si y Hospi al, Tampe e, Finland (Recei ed 29 Sep embe 2014; Accep ed 7 Decembe 2014) Abs ac : The Finnish Medical Socie y Duodecim ini ia ed and managed he upda e o he Finnish na ional guideline o ch onic obs uc i e pulmona y disease (COPD). The Finnish COPD guideline was e ised o acknowledge he p og ess in diagnosis and managemen o COPD. This Finnish COPD guideline in English language is a pa o he o iginal guideline and ocuses on he diagnosis, assessmen and pha maco he apy o s able COPD. I is in ended o be used mainly in p ima y heal h ca e bu no o - ge ing espi a o y specialis s and o he heal hca e wo ke s. The new ecommenda ions and s a emen s a e based on he bes e i- dence a ailable om he medical li e a u e, o he published na ional guidelines and he GOLD (Global Ini ia i e o Ch onic Obs uc i e Lung Disease) epo . This guideline in oduces he diagnos ic app oach, di e en ial diagnos ics owa ds as hma, assessmen and ea men s a egy o con ol symp oms and o p e en exace ba ions. The pha maco he apy is based on he symp- oms and a clinical pheno ype o he indi idual pa ien . The guideline de ines h ee clinically ele an pheno ypes including he low and high exace ba ion isk pheno ypes and he neglec ed as hma–COPD o e lap synd ome (ACOS). These clinical pheno- ypes can help clinicians o iden i y pa ien s ha espond o speci ic pha macological in e en ions. Fo he low exace ba ion isk pheno ype, pha maco he apy wi h sho -ac ing b 2 -agonis s (salbu amol, e bu aline) o an icholine gics (ip a opium) o hei com- bina ion ( eno e ol–ip a opium) is ecommended in pa ien s wi h less symp oms. I sho -ac ing b onchodila o s a e no enough o con ol symp oms, a long-ac ing b 2 -agonis ( o mo e ol, indaca e ol, oloda e ol o salme e ol) o a long-ac ing an icholine gic (musca inic ecep o an agonis s; aclidinium, glycopy onium, io opium, umeclidinium) o hei combina ion is ecommended. Fo he high exace ba ion isk pheno ype, pha maco he apy wi h a long-ac ing an icholine gic o a ixed combina ion o an inhaled glucoco icoid and a long-ac ing b 2 -agonis (budesonide– o mo e ol, beclome hasone dip opiona e– o mo e ol, lu icasone p opiona e–salme e ol o lu icasone u oa e– ilan e ol) is ecommended as a i s choice. O he ea men op ions o his pheno- ype include combina ion o long-ac ing b onchodila o s gi en om sepa a e inhale s o as a ixed combina ion (glycopy oni- um–indaca e ol o umeclidinium– ilan e ol) o a iple combina ion o an inhaled glucoco icoid, a long-ac ing b 2 -agonis and a long-ac ing an icholine gic. I he pa ien has se e e- o- e y se e e COPD (FEV 1 <50% p edic ed), ch onic b onchi is and e- quen exace ba ions despi e long-ac ing b onchodila o s, he pha maco he apy may include also o lumilas . ACOS is a pheno ype o COPD in which he e a e ea u es ha comply wi h bo h as hma and COPD. Pa ien s belonging o his pheno ype ha e usu- ally been excluded om s udies e alua ing he e ec s o d ugs bo h in as hma and in COPD. Thus, e idence-based ecommenda- ion o ea men canno be gi en. The ea men should co e bo h diseases. Gene ally, he he apy should include a leas inhaled glucoco icoids (beclome hasone dip opiona e, budesonide, ciclesonide, lu icasone u oa e, lu icasone p opiona e o mo- me asone) combined wi h a long-ac ing b onchodila o (b 2 -agonis o an icholine gic o bo h). The Finnish Medical Socie y Duodecim has c ea ed a sys em o he p oduc ion o na ional guidelines on he mos impo - an diseases. These guidelines p o ide he basis o e idence- based ea men o abou 100 common heal h p oblems and a e based on a igo ous e alua ion o e idence and p oduc ion o he guidelines in a speci ic o ma including o mal le el o e idence s a emen s (A–D; see able 1) [1], and his le el o e idence is also e e ed in he cu en MiniRe iew. The majo di e ence be ween he cu en guideline and mos o he guide- lines o ch onic obs uc i e pulmona y disease (COPD) is ha he sho e iews o he li e a u e p esen ing he e idence sup- po ing he claim o a ce ain le el o e idence (A–D) a e publicly a ailable [1,2]. These guidelines and s a emen s (in he Finnish language) a e published on he websi e o he medical socie y Duodecim [1,2] and a e a ailable o all physi- cians as well as o he gene al public in Finland. In addi ion, pa ien e sions a e occasionally published. Du ing summe 2012, he Finnish Medical Socie y Duodecim and he Finnish Au ho o co espondence: Hannu Kankaan an a, Depa men o Respi a o y Medicine, Sein€ ajoki Cen al Hospi al, 60220 Sein€ ajoki, Finland ( ax +358 6 415 4989, e-mail [email p o ec ed]). ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses. Basic & Clinical Pha macology & Toxicology, 2015, 116, 291–307 Doi: 10.1111/bcp .12366 Respi a o y Socie y in i ed membe s o a g oup aiming o upda e he p e ious guideline on COPD. The p oduc ion o he no el guideline was s a ed in Oc obe 2012, and he inal e sion o he guideline (in Finnish) was accep ed and pub- lished on 13 June 2014 a e a long e iew p ocess [2]. In Finland, he diagnos ics and ea men o common espi- a o y diseases such as as hma and COPD a e mainly pe - o med in p ima y heal h ca e by gene al p ac i ione s, and only a pa o he pa ien s a e ea ed by espi a o y specialis s. The Finnish Medical Socie y Duodecim ep esen s he whole medical communi y in Finland, and he socie y necessi a es ha he guideline should se e especially he gene al p ac i io- ne s wo king in p ima y heal h ca e. Howe e , he guideline is also widely used by espi a o y specialis s and o he heal hca e specialis s such as nu ses and pha macis s. Thus, he main equi emen s o he guideline we e ha i should be e idence based, accu a e, clea and simple enough o be used in a busy gene al p ac ice. The need o upda e he guideline o he ea men o COPD was a oused by he p e alence o COPD in he Finnish pa ien s and i s impo ance and cos s o pa ien s and o he heal hca e sys em as well as he pa adigm shi in he ea - men o COPD s a ed by he GOLD (Global Ini ia i e o Ch onic Obs uc i e Lung Disease) epo [3]. This guideline g ea ly owes o he in e na ional GOLD epo [3] as well as o he inno a i e guideline o COPD by he Spanish Respi a- o y Socie y [4]. The p esen guideline in oduces a modi ied and hope ully, simpli ied e sion o pha macological ea men based on he assessmen o exace ba ion isk p esen ed in he GOLD epo [3] and Spanish guideline [4]. I akes in o he accoun he neglec ed pheno ype o COPD–as hma as p e- sen ed in he Spanish COPD guideline [4,5] o as hma–COPD o e lap synd ome (ACOS) as e med by he ecen GINA epo [6]. As hma and COPD a e gene ally diagnosed, ea ed and managed by he same pe sonnel (nu ses and gene al p ac- i ione s) in Finland. As he e a e some c ucial di e ences in he ea men o hese wo common diseases, accu a e diagno- sis and clea ea men guidelines a e o u mos impo ance. Thus, in he p epa a ion o he p esen guideline, he diagnos- ic sec ion was co-o dina ed wi h he ecen ly published as hma guideline as h ee membe s se ed in his g oup (H.K., T.H. and L.L.) who we e also in ol ed in he p oduc ion o he as hma guideline [7]. Special a en ion was d awn o he diagnosis o COPD, di e en ial diagnosis be ween as hma and COPD, and he inclusion o he ACOS. In addi ion, he pha - macological ea men sec ion was de eloped o pu sue eadi- ness, simplici y and in-dep h p ecision a he same ime. This Finnish COPD guideline in he English language co e s only a pa o he o iginal guideline [2,8,9], ha is he diagnos ics, comp ehensi e assessmen and pha macological ea men o s able COPD. O he sec ions such as epidemiology, sc eening, obacco cessa ion, oxygen he apy, en ila o y suppo , su gi- cal ea men s, pulmona y ehabili a ion, managemen o acu e exace ba ions and pallia i e ca e can be ound in he o iginal documen in Finnish [2,9]. This e sion o he guideline has been upda ed o con ain some no el compounds (e.g. umeclid- inium), ixed combina ions o long-ac ing b onchodila o s (glycopy onium–indaca e ol and umeclidinium– ilan e ol) and ixed combina ions o inhaled glucoco icoids (ICS) and long- ac ing b 2 -agonis s (beclome hasone dip opiona e– o mo e ol and lu icasone u oa e– ilan e ol) no included in he ea lie published Finnish e sion [2,8] and now a ailable in Finland. In addi ion, new ele an li e a u e has been ci ed. Diagnos ics The diagnosis o COPD is based on ele an exposu e his o y, symp oms and ai way obs uc ion ha is no ully e e sible (pos -b onchodila o o ced expi a o y olume in one-second/ o ced i al capaci y <0.70; FEV 1 /FVC <0.70). E alua ion o p edisposing ac o s. The ollowing p edisposing ac o s should be assessed in he diagnos ic e alua ion: smoking his o y (in pack-yea s), cu en smoking, passi e smoking, occupa ional exposu es, p e ious espi a o y in ec ions, as hma and espi a o y diseases in he amily. Symp oms. Typical symp oms o COPD include dyspnoea, ches igh - ness, wheezing, cough and spu um p oduc ion [3], bu he diagnosis o COPD canno be based on symp oms alone, as some pa ien s a e symp om ee and simila symp oms can be caused by o he diseases [10]. Howe e , symp oms sug- ges i e o COPD in an indi idual wi h exposu e o obacco o o he isk ac o s should lead o spi ome y and o he diagnos ic e alua ions. In pa ien s wi h es ablished COPD, he le el o symp oms and he p esence o exace ba ions should be assessed as hese a e used o guide he ea men Table 1. G ading o he e idence in he Cu en Ca e Guidelines. Le el o e idence Desc ip ion ( e bal exp ession in he ex ) A S ong esea ch-based e idence (mul iple, ele an , high-quali y s udies wi h homogeneous esul s –e.g. wo o mo e andomized, con olled ials o a sys ema ic e iew wi h clea ly posi i e esul s) B Mode a e e idence (e.g. one andomized, con olled ial o mul iple adequa e s udies) (...appa en ly...) C Limi ed esea ch-based e idence (e.g. con olled, p ospec i e s udies) (...may...) D No e idence (e.g. e ospec i e s udies o he consensus eached in he absence o good-quali y e idence) Adap ed om e e ence [1]. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). 292 HANNU KANKAANRANTA ET AL. MiniRe iew [3]. COPD is a p og essi e disease and symp oms end o wo sen, especially i he pa ien con inues smoking, and dyspnoea a es o ligh exe cise, cough, weigh loss and e- quen exace ba ions a e o en p esen in ad anced se e e- o- e y se e e COPD [11]. Physical examina ion. The diagnosis o COPD canno be based on clinical signs, bu hese can be sugges i e o COPD and i s deg ee o se e i y [3]. Wheezing may be hea d du ing auscul a ion o he ches , bu pulmona y sounds can also be no mal. Inc eased espi a- o y a e a es , he use o accesso y espi a o y muscles and signs o igh -sided hea ailu e may be p esen in se e e COPD. Pulmona y unc ion es ing. In diagnosing COPD, spi ome y should be conduc ed wi h b onchodila ion es . COPD can be diagnosed i FEV 1 /FVC is <0.70 in a pos -b onchodila ion spi ome y [3]. This c i e ion causes some o e -diagnosis in elde ly people [12,13] and possibly also in women [14] and unde diagno- sis in indi iduals younge han 45 yea s [13], bu i is sen- si i e in de ec ing COPD clinically assessed by a physician [15–17]. This c i e ion is also associa ed wi h mo ali y isk [18]. Signi ican e e sibili y in he b onchodila ion es (FEV 1 inc eases a leas 12% and 200 ml) can be de ec ed in app oxi- ma ely 25–50% o indi iduals wi h COPD (see Di e en ial diagnosis below). Classi ica ion o se e i y o ai way obs uc- ion is p esen ed in able 2, bu his is only one aspec o he clinical se e i y o COPD. Radiological imaging. The diagnosis o COPD canno be based on ches X- ay, bu a ches X- ay should be included in he ini ial e alua ion o exclude o he diseases such as pulmona y cance , ube culosis, pneumonia, hea ailu e and pleu al diseases. In mild COPD, ches X- ay is almos always no mal. In ad anced disease la ening o he diaph agm, long na ow hea , o e -in la ion wi h hinning o blood essels and emphysema ous bullae can be seen. Compu e ized omog aphy o he ches is no ou inely needed, bu may be used by spe- cialis s in cases o p oblema ic di e en ial diagnosis o de ec b onchiec asis and in he e alua ion o su gical ea men o COPD [19]. Blood es s and spu um cul u es. The e a e no speci ic blood es s o be used in diagnosing COPD, bu some basic es s may be used o ule ou o he dis- eases and o assess in ec ions and espi a o y ailu e du ing acu e exace ba ions. Bac e ial cul u e o spu um is no use ul in s able COPD. I COPD is ound in a pe son wi h excep ion- ally young age (<45 yea s) o wi h a low smoking his o y (<20 pack-yea s), se um le els o alpha-1-an i ypsin (A1AT) should be measu ed o ule ou alpha-1-an i ypsin de iciency. This ecommenda ion may di e om ha o o he guidelines [3]. Howe e , sc eening o A1AT is no ecommended o all pa ien s in Finland, because he e is no A1AT eplacemen he apy a ailable in Finland. Thus he only ele an he apeu- ic op ion is counselling o smoking cessa ion and he smok- ing cessa ion is ecommended o all pa ien s wi h COPD despi e he knowledge o A1AT le els. Comp ehensi e e alua ion o he pa ien . Symp oms, quali y o li e and he impac o he disease can be assessed wi h alida ed ques ionnai es such as COPD Assessmen Tes â (CAT â ) and modi ied Medical Resea ch Council Dyspnea Scale (mMRC) [3]. Six-minu e walking es o e gome y can be used o assess exe cise ole ance. The clinical se e i y o COPD is assessed based on he deg ee o ai way obs uc ion, le el o symp oms, exace ba ions and co-mo bidi ies ( able 2). Ex a-pulmona y mani es a ions and co-mo bidi ies such as ca dio ascula diseases, me abolic synd ome, os eopo osis and dep ession a e mo e p e alen in indi iduals wi h COPD han in non-COPD indi iduals wi h Table 2. Classi ica ion o he se e i y o obs uc ion and he clinical se e i y o ch onic obs uc i e pulmona y disease (COPD). Se e i y o obs uc ion (assessed a e b onchodila ion) Clinical se e i y o COPD Mild FEV 1 ≥80% p edic ed Good quali y o li e (CAT â <10), no equen exace ba ions and FEV 1 >50% p edic ed Mode a e 50% ≤FEV 1 <80% One o he ollowing: FEV 1 <50% p edic ed A leas wo exace ba ions a yea o one hospi aliza ion because o COPD COPD has a medium impac on li e (e.g. CAT â ≥10 poin s) o causes poo quali y o li e o impai ed exe cise ole ance Se e e 30% ≤FEV 1 <50% Ve y se e e FEV 1 <30% One o he ollowing: FEV 1 <30% p edic ed Ch onic espi a o y ailu e F equen exace ba ions o hospi aliza ions ega dless o ea men o COPD COPD has a high o e y high impac on li e (e.g. CAT â ≥20 poin s) o causes e y poo quali y o li e o exe cise ole ance ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). MiniRe iew FINNISH COPD GUIDELINE 293 simila smoking his o y. Nu i ional s a us and especially unin- ended loss o weigh should be assessed. Di e en ial diagnosis. The mos impo an di e en ial diagnoses include as hma, ch onic b onchi is, lowe ai way in ec ions (including ube cu- losis), lung cance , in e s i ial lung diseases and hea diseases. A common diagnos ic p oblem is o dis inguish be ween as hma and COPD. Al hough hese diseases a e o en ea ed wi h he same medica ion, hey di e in basic pa hology, ae iology and p ognosis. COPD and as hma a e o en ound in he same indi idual, and in smoking as hma pa ien s, he cel- lula componen s o in lamma ion may esemble ha ound in COPD [3,6]. The di e en ial diagnosis o as hma and COPD canno be based on pulmona y unc ion es s alone, bu a com- p ehensi e app oach including smoking his o y, symp oms, co-mo bidi ies and amily his o y is needed [3,6]. B onchodila ion es in spi ome y canno eliably dis in- guish be ween as hma and COPD [3], as as hma ic indi iduals do no always p esen wi h signi ican e e sibili y and app oxima ely 25–50% o indi iduals wi h COPD ha e signi - ican e e sibili y [20–22]. Glucoco icoid he apy es does no always di e en ia e be ween as hma and COPD [23], as a conside able p opo ion o indi iduals wi h COPD bene i om ICS [24]. On he o he hand, some o he as hma ic indi iduals a e no esponsi e o ICS alone [25]. Howe e , i an indi idual pa ien clea ly bene- i s om using ICS (i.e. as assessed based on imp o emen in lung unc ion o based on a educ ion o symp oms o exace - ba ions), i should be con inued ega dless o he diagnosis (as hma o COPD). As he esponse o o al glucoco icoids does no p edic esponsi eness o ICS [26,27], he possible ea men ials should be conduc ed using ICS a mode a e ( o high) doses o (4 o) 8 weeks. No maliza ion o lung unc ion by ICS ea men excludes COPD and s ongly suppo s he diagnosis o as hma. I he lung unc ion is no signi ican ly changed by ICS ea men , he diagnosis is mo e likely COPD han as hma. Aims o he T ea men o COPD The goals o he he apy o COPD can be di ided in o ou majo aims: 1Con olling symp oms and imp o ing he quali y o li e. 2Reducing u u e isk, ha is p e en ing exace ba ions. 3Slowing down he p og ession o he disease. 4Reducing mo ali y. Mul imodal The apy o COPD The he apy o COPD includes bo h non-pha macological and pha macological means. Non-pha macological ea men modali ies include smoking cessa ion [28], oxygen he apy, physical exe cise and pulmona y ehabili a ion, en ila o sup- po and su gical he apy. Pallia i e ca e in pa ien s nea ing dea h is discussed in de ail in he o iginal documen and may include a ial o opioids o e ac o y dyspnoea [2,9]. The isk o physical inac i i y in pa ien s wi h COPD is as ly inc eased (A) [29], and he pa ien s should be encou aged o do physical exe cise. Physical ac i i y educes he isk o mo - ali y and hospi aliza ions. In con as , physical inac i i y p e- dic s inc eased mo ali y (A) [30,31]. Exe cise-based pulmona y ehabili a ion cou ses should be a ailable o COPD pa ien s wi h con inued dyspnoea despi e he use o b onchodila o s, o when hey a e physically inac i e and su - e om equen exace ba ions, o ha e exe cise in ole ance. These ecommenda ions can be ound in de ail in he o iginal documen [2,8,9]. Pha macological he apies include b on- chodila o s, combina ions o ICS and long-ac ing b onchodila- o s, phosphodies e ase 4 (PDE4) inhibi o s o heophylline and in luenza and pneumococcal accina ion. Vaccina ion In he gene al popula ion, accina ion o pe sons aged >65 yea s agains in luenza has been ound o educe pneumo- nia, hospi aliza ion and dea hs by 50–68%. A majo i y o pa ien s wi h COPD belong o his age g oup. Vaccina ion agains in luenza educes COPD exace ba ions (A) [32]. Vac- cina ion annually agains in luenza is ecommended o all pa ien s wi h COPD. Pneumococcal accina ion appa en ly educes pneumonia o pneumococcal o igin in pa ien s wi h COPD (B) [33–35]. Pneumococcal accina ion is ecommended o pa ien s wi h COPD. Pha maco he apy o S able COPD P inciples o egula long- e m pha maco he apy o COPD. 1The e exis wo main goals wi h he cu en pha maco he - apy o COPD. They a e (1) o con ol symp oms and (2) o educe u u e isk (i.e. he exace ba ions o COPD). The g ounds o he use o any pa icula ea men in COPD may be ei he one o hese goals o bo h goals oge he . The con inua ion o e mina ion o a speci ic he apy is decided based on which goal is a ge ed ( ig. 1). 2I a pa icula pha maco he apy is s a ed in an e o o achie e bo h goals, he decision whe he o con inue o discon inue is made based on goal 2, ha is he aim o educe u u e isk (exace ba ions). This is because he abil- i y o inabili y o any pa icula d ug o imp o e lung unc ion o symp oms is no known o p edic i s abili y o educe exace ba ions o COPD. 3The pha macological g oups o inhaled d ugs and he com- pounds used in he pha maco he apy o COPD a e shown in able 3. 4The e ec s o se e al pha maco he apies o COPD as well as he e ec s o smoking cessa ion and exe cise on di e - en end-poin s and goals in he ea men o COPD a e shown in able 4. 5The pha maco he apy o COPD is based on he indi idual pa ien pheno ype, on he le el o symp oms and he isk o exace ba ions. These a e desc ibed in he sec ion ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). 294 HANNU KANKAANRANTA ET AL. MiniRe iew ‘COPD pheno ypes and pheno ype-speci ic pha maco he apy o COPD’. G ouping o pa ien s o h ee di e en pheno- ypes is shown in ig. 2. 6Pheno ype and pheno ype-based pha maco he apy ( ig. 2) should be e alua ed a e e y isi o heal h ca e as he pheno ype may change when he disease p og esses (espe- cially wi h ega d o an inc ease in exace ba ion isk) [36]. 7So a , no pha maco he apy has de ini i ely been shown o slow down disease p og ession (annual FEV 1 decline) o educe mo ali y [37–43], e en hough p elimina y indings sugges ing such e ec s ha e been published. 8The p inciples o combining di e en d ugs in he ea - men o COPD a e shown in able 5. 9A sho -ac ing b onchodila o o be used on as-needed basis is conside ed bene icial o mos pa ien s ea ed wi h long-ac ing b onchodila o s o combina ion he apy includ- ing long-ac ing b onchodila o s. B onchodila o s. D ugs ha elie e b onchial obs uc ion by educing b onchial smoo h muscle con ac ion a e called b onchodila o s. Usually, hey imp o e spi ome ic alues e lec ing obs uc ion such as FEV 1 . These compounds gene ally imp o e also emp ying o he lungs and educe ai apping (dynamic hype in la ion/ es ic ion) bo h a es and du ing exe cise [44]. These e ec s canno be p edic ed based on he abili y o he pa icula com- pound o imp o e FEV 1 [45–48]. The dose– esponse e ec o all b onchodila o s a he cu en ly used doses is ela i ely la , which means ha a small inc ease (e.g. doubling) in he dose is no expec ed o p oduce a as inc ease in he b onchodila o y ac ion [49–51]. The ad e se e ec s a e gene ally dose- ela ed. Inc ease in he dose o sho -ac ing inhaled b 2 -agonis and an i- choline gic, especially when gi en nebulized, may elie e sub- jec i e dyspnoea in acu e se ing du ing an exace ba ion o COPD bu may no help as a long- e m he apy [52,53]. B onchodila o s can be di ided in o sho ac ing (du a ion o b onchodila o y e ec gene ally 3–6 h ) and long ac ing (du a ion o b onchodila o y e ec gene ally 12–24 h ). The e a e wo di e en classes o b onchodila o s ha ha e basically simila b onchodila o y ac ion in he ea men o COPD bu di e en mechanism o ac ion. These pha macological classes a e b 2 -agonis s and musca inic ecep o (M 1 ,M 2 and M 3 ) an agonis s ( e med an icholine gics) [54,55]. Bo h o hese pha macological classes con ain sho -ac ing and long-ac ing p epa a ions. B onchodila o s a e usually adminis e ed on ei he as-needed (usually sho -ac ing p epa a ions) o egu- la ly (usually long-ac ing p epa a ions) o ea o p e en he occu ence o symp oms. A sho -ac ing b onchodila o o be used as-needed is con- side ed bene icial o mos pa ien s e en hough hey we e ea ed wi h long-ac ing b onchodila o s o combina ion he - apy including long-ac ing b onchodila o s. Ins ead, he use o egula , high-dose (nebulized, e c.), sho -ac ing b onchodila o o hei combina ion in pa ien s ea ed wi h long-ac ing b on- chodila o s is no e idence based [3] and should only be ese ed o ea men o he mos di icul cases. In such a si - ua ion, he need o long-ac ing b onchodila o s should be ca e ully e alua ed as well as he abili y o he pa ien o p op- e ly inhale hem. Sho - and long-ac ing b 2 -agonis s (SABA, LABA). The main bene icial e ec o b 2 -agonis s is he educ ion o b onchial smoo h muscle con ac ion ha leads o elie o b onchial obs uc ion. The du a ion o he e ec o sho -ac - ing b 2 -agonis s is usually 3–6 h . Sho -ac ing b 2 -agonis used ei he as-needed o egula ly educe symp oms o COPD and imp o e lung unc ion [56]. The e ec o long-ac ing b 2 - Long- e m pha macological ea men o COPD has wo sepa a e aims, bu same medica ion may help in achie ing he apeu ic bene i in bo h aims. Aim 1: Con olling symp oms B onchodila ion; educ ion o symp oms ei he sho - e m o long- e m • SABA: eno e ol, salbu amol, e bu aline • SAMA: ip a opium • LABA: o mo e ol, indaca e ol, oloda e ol, salme e ol • LAMA: aclidinium, glycopy onium, io opium, umeclidinium • Teophylline (?) Aim 2: Reducing u u e isk P e en ing u u e exace ba ions o COPD • LAMA: Tio opium, aclidinium, glycopy onium, umeclidinium • ICS + LABA • LABA: salme e ol, o mo e ol, oloda e ol, indaca e ol • LABA + LAMA • Ro lumilas How o e alua e he e ec i eness o he medica ion and how o decide whe he o s op o con inue medica ion? E alua e i s whe he he gi en medica ion is used o achie e aim 1 o aim 2. I he gi en d ug is used o achie e bo h aims, he decision whe he o no o con inue is made based on he c i e ia shown o he aim 2. Aim 1: One o mo e o he ollowing indings in he absence o se e e ad e se e en s suppo he con inua ion o he gi en medica ion • Reduc ion in daily symp oms • symp om assessmen e.g. by CAT®- es • Imp o emen in exe cise ole ance • Imp o emen in objec i e lung unc ion measu emen s (e.g. FEV1, FVC o PEF; howe e , his is no a p e equisi e o con inue medica ion) Aim 2: One o mo e o he ollowing indings suppo s s opping he medica ion: • Appea ance o a se e e ad e se e ec • Appea ance o a mild o mode a e ad e se e ec ha is equen and/o a ec s he quali y o li e (e.g. epea ing episodes o candidiasis o dia hoea) and disappea s a e s opping he medica ion • O no e! Lack o imp o emen in symp oms o lung unc ion is no a eason o s op medica ion! Fig. 1. Aims o he pha maco he apy o ch onic obs uc i e pulmona y disease (COPD) and p inciples o he e alua ion whe he o con inue o discon inue he cu en medica ion. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). MiniRe iew FINNISH COPD GUIDELINE 295 agonis s las s 12 h ( o mo e ol o salme e ol) o 24 h (ind- aca e ol, oloda e ol o ilan e ol). The b onchodila o y ac ion o o mo e ol/indaca e ol/oloda e ol/ ilan e ol s a s soone (wi hin 5 min.) han ha o salme e ol (wi hin 20–30 min.). Indaca e ol imp o es lung unc ion (e.g. FEV 1 ), educes dysp- noea du ing exe cise and imp o es he quali y o li e, bu he e idence on he educ ion o COPD exace ba ions is s ill p eli- mina y [57–60]. The e icacy o indaca e ol, oloda e ol o i- lan e ol, when measu ed using FEV 1 o quali y o li e, is a leas as good as ha o o mo e ol o salme e ol [58,61–63] o he long-ac ing an icholine gic io opium [58,61,64]. Gene ally, b 2 -agonis s a e well ole a ed. Typical ad e se e ec s include emo , achyca dia and palpi a ions ha ha e been epo ed in <1% o pa ien s. Headache, muscula c amps and an inc ease in he blood glucose and a dec ease in po assium le els a e possible, e en hough hese e en s occu almos as o en in pa ien s ea ed wi h placebo [65]. I has been sugges ed ha ac i a ion o hea b 2 - ecep o s by b 2 -agonis s migh induce ischaemia, ca diac insu iciency and a hy hmias o inc ease he isk o sudden dea h. How- e e , in con olled clinical s udies ec ui ing pa ien s wi h COPD, he e is no indica ion o he inc ease o a hy hmias o ca diac dea hs [65] o o e all mo ali y [66] by b 2 -agon- is s. Based on a case–con ol s udy [67], an inc ease in he isk o se e e a hy hmias is possible. Thus, he bene i s o using long-ac ing b 2 -agonis in pa ien s wi h se e e ca diac disease should be ca e ully conside ed. The use o long-ac ing b 2 -agonis s in he ea men o as hma in he absence o simul aneous ICS is p ohibi ed [7] because he e is e idence ha ea men o as hma wi h long- ac ing b 2 -agonis s in he absence o ICS inc eases mo ali y due o as hma [68]. In con as , in he ea men o COPD, a long-ac ing b 2 -agonis can be used as he sole he apy as i does no inc ease mo ali y in COPD acco ding o he s udies published [65,66]. Acco ding o some coho s udies, use o long-ac ing b 2 -agonis may e en educe he mo ali y o pa ien s wi h COPD [69,70]. Sho - and long-ac ing an icholine gics (SAMA, LAMA). An icholine gic compounds block musca inic ecep o s (M 1 ,M 2 and M 3 ), hus an agonizing ace ylcholine-induced b onchial smoo h muscle con ac ion. The du a ion o he e ec o sho -ac ing an icholine gic (ip a opium) is usually somewha longe (e en up o 8 h ) han ha o he sho -ac - ing b 2 -agonis s (3–6 h ), bu s a s mo e slowly [54,55]. The e ec o long-ac ing an icholine gics las s ei he 12 h (aclidi- nium) o app oxima ely 24 h (glycopy onium, io opium o umeclidinium). O hese, io opium has been mos ex ensi ely s udied and used. The b onchodila o y ac ion o aclidinium and glycopy onium s a s soone han ha o io opium. Tio opium imp o es lung unc ion and quali y o li e and educes symp oms and exace ba ions o COPD (A) [71]. In con as , io opium does no a ec he p og ession o he dis- ease as judged by he annual decline in FEV 1 [72]. Tio opium may be mo e e ec i e han salme e ol in educing exace ba- ions o COPD [73]. Bo h aclidinium and glycopy onium ha e been shown o induce b onchodila ion, imp o e lung unc ion and quali y o li e and educe he need o escue medica ion [74,75], and hei e icacy oughly equals o ha o io opium. Aclidinium, glycopy onium and umeclidinium ha e been shown o educe COPD exace ba ions in s udies las ing up o 1 yea [76–78], bu long- e m s udies las ing mo e han 1 yea , simila o hose made wi h io opium [72,73], a e s ill lacking. Inhaled an icholine gics a e gene ally well ole a ed, and ad e se e ec s occu ela i ely seldom. Typical ad e se e ec s, such as d y mou h, blu ed ision, h oa i i a ion, hi- ni is, cons ipa ion and nausea, a e due o blocking o musca- inic ecep o s. O he possible ad e se e ec s include also a hy hmias, u ina y e en ion/obs uc ion, ele a ed in aocula p essu e and acu e o wo sening o na ow-angle glaucoma [79]. The sho -ac ing an icholine gic ip a opium has been sus- pec ed o induce ca diac ad e se e ec s [79]. Wi h he long- ac ing an icholine gics, no simila inc ease in ca diac ad e se e ec s has been epo ed wi h ce ain y [79]. The 4-yea -long UPLIFT ial epo ed ha he e we e s a is ically signi ican ly less ca diac ad e se e ec s and he o al mo ali y was nume i- cally, al hough no s a is ically, lowe in pa ien s ea ed wi h io opium [72]. Recen ly, i has been p oposed ha dosing o io opium wi h Respima â de ice (Boeh inge Ingelheim, Ingelheim, Table 3. Pha macological compounds used in he he apy o ch onic obs uc i e pulmona y disease. Pha macological g oup and i s abb e ia ion Compounds belonging o he g oup Sho -ac ing b 2 -agonis s Salbu amol Te bu aline Long-ac ing b 2 -agonis (LABA) Fo mo e ol Indaca e ol Oloda e ol Salme e ol Vilan e ol Sho -ac ing an icholine gic Ip a opium Long-ac ing an icholine gic (LAMA) Aclidinium Glycopy onium Tio opium Umeclidinium Inhaled glucoco icoids (ICS) Beclome hasone dip opiona e Budesonide Ciclesonide Flu icasone p opiona e Flu icasone u oa e Mome asone Fixed combina ion o inhaled glucoco icoid and long-ac ing b 2 -agonis (ICS +LABA) Budesonide– o mo e ol Beclome hasone dip opiona e– o mo e ol Flu icasone p opiona e–salme e ol Flu icasone u oa e– ilan e ol Fixed combina ion o long-ac ing an icholine gic and long-ac ing b 2 -agonis (LAMA +LABA) Glycopy onium–indaca e ol Umeclidinium– ilan e ol Phosphodies e ase 4 (PDE4) inhibi o s Ro lumilas O he s Theophylline ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). 296 HANNU KANKAANRANTA ET AL. MiniRe iew Table 4. E ec s o smoking cessa ion, exe cise and a ious pha maco he apies in he ea men o ch onic obs uc i e pulmona y disease (COPD). Smoking cessa ion Exe cise Sho -ac ing b onchodila o (b 2 -agonis o an icholine gic) Long-ac ing b 2 -agonis Long-ac ing an icholine gic Addi ion o inhaled glucoco icoid in se e e COPD 1 Ro lumilas in se e e COPD Symp oms ++ + + + (+) Obs uc ion ++++ (+)(+) Exace ba ions ++ ++ + + Disease p og ession (annual FEV 1 decline) +? (+)? Mo ali y ++  (+)? +: de ini e bene icial e ec ; (+): small o possible bene icial e ec ; : no e ec ; ?: no e idence. 1 In p ac ice means e mina ing long-ac ing b 2 -agonis and p esc ibing a combina ion p oduc con aining bo h inhaled glucoco icoid and long-ac ing b 2 -agonis . Is i as hma-COPD o e lap? Low exace ba ion isk As hma-COPD o e lap synd ome (ACOS) High exace ba ion isk When should COPD be suspec ed? • Pos -b onchodila aon FEV1/FVC < 0.7 in spi ome y • Risk ac o s: smoking his o y > 10 pack-yea s (somemes long- e m hea y exposu e o dus o alpha-1- an ypsin deficiency) • Symp oms ypical o COPD: cough, spu um p oducon, dyspnoea (in exe cise), wheezing – O no e: some o he paen s a e asymp omac Is i un- ea ed as hma? • I obs ucon can be o ally e e sed (FEV1/FVC ≥ 0.7) wi h ea men (inhaled glucoco coid, long-acng β2-agonis can be added) is no COPD • Conside whe he he c i e ia o as hma is me Diagnose COPD i • Despi e possible he apy, obs ucon (pos -b onchodila o FEV1/FVC < 0.7) emains • The e is idenfiable isk- ac o o COPD (smoking > 10 pack-yea s, hea y long- e m dus exposu e o alpha-1-an ypsin deficiency) • Disease p esen aon con o ms COPD (e.g. no un ea ed as hma) • The paen may ha e bo h COPD and as hma (see below) T ea men o all paen s wi h COPD • Smoking cessaon • F equen exe cise (conside special pulmona y ehabili aon) • Vaccinaon: influenza (yea ly), pneumococcal Pheno ype- specific he apy • Is i as hma-COPD o e lap synd ome (ACOS)? • Wha is he exace baon isk? Has he e been ≥ 2 COPD exace ba ions o one leading o hospi aliza ion du ing las yea o is FEV1< 50 % p edic ed ? see c i e ia D ug he apy is a combina ion om COPD and as hma guidelines No ice bo h diseases! Gene ally, medica ion includes a leas he ollowing •ICS + LABA o •ICS + LABA + LAMA T y hese, combina ion possible Conside isks and bene i s indi idually •LAMA •ICS + LABA •LAMA + LABA •Ro lumilas (i equen exace ba ions, ch onic b onchi is and FEV1< 50 % p edic ed) Less symp oms (CAT®sco e <10) •SABA and/o SAMA as needed Mo e symp oms (CAT®sco e ≥10) •Daily LABA and/o LAMA •Conside al e na i e diagnosis, especially ca diac disease •(Theophylline) C i e ia o as hma-COPD o e lap synd ome 2 main c i e ia, o 1 main and 2 addi ional c i e ia Main c i e ia • Signi ican b onchodila o y esponse (FEV1> 15 % and > 400 ml) • Spu um eosinophilia o ele a ed (>50 ppb) exhaled NO • P e ious as hma symp oms (s a ing age a < 40 y) Addi ional c i e ia • Ele a ed o al IgE • A opy • Repea ed signi ican b onchodila o y esponse (FEV1> 12 % and > 200 ml) • PEF- ollow-up ypical o as hma Conside e e al o espi a o y specialis • The e a e diagnosc p oblems • The e a e he apeuc p oblems • The abili y o wo k is in queson • Long- e m oxygen he apy is conside ed (SaO2< 90 % a es and s opped smoking) Fig. 2. The p inciples o diagnos ics and pheno ype-speci ic he apy o ch onic obs uc i e pulmona y disease (COPD). O no e, he cu en indica- ion o he use o di e en ixed combina ions o inhaled glucoco icoid ICS and long-ac ing b 2 -agonis (LABA) in COPD is equen exace ba- ions despi e he use o app op ia e b onchodila o he apy, bu he FEV 1 anges om <50% p edic ed (budesonide– o mo e ol, beclome hasone dip opiona e– o mo e ol) o <60% p edic ed ( lu icasone p opiona e–salme e ol) and o <70% p edic ed ( lu icasone u oa e– ilan e ol). ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). MiniRe iew FINNISH COPD GUIDELINE 297 Ge many) would cause mo e dea hs han i s dosing wi h Handihale â de ice (Boeh inge Ingelheim, Ingelheim, Ge many) [79]. Howe e , a di ec compa ison o he wo de ices o a mean o 2.3 yea s indica ed ha he e we e no di e ences in mo ali y, se ious ca diac ad e se e ec s o exace ba ions o COPD [80]. Combina ion b onchodila o he apy. B onchodila o s wi h a di e en mechanism o du a ion o ac ion can be ela i ely eely combined ( able 5), and he combina ion may ha e a be e b onchodila o y e ec [81]. Fo example, combina ion o a sho -ac ing an icholine gic wi h a sho - o long-ac ing b 2 -agonis imp o es FEV 1 be e han any o he single agen s [81,82]. Sho - o long-ac ing b 2 - agonis can be combined wi h a long-ac ing an icholine gic i a single agen is no imp o ing symp oms enough [81–83]. The combina ion o io opium and a long-ac ing b 2 -agonis appa en ly imp o es he lung unc ion and quali y o li e somewha be e han io opium alone (B) [83]. The use o sho - and long-ac ing an icholine gic compounds oge he is no ecommended. E en hough his combina ion may imp o e esul s o lung unc ion es s be e han he single agen s, i will inc ease he isk o ad e se e ec s such as u ina y e en- ion [84]. Combina ion o a sho -ac ing b 2 -agonis wi h a long-ac ing an icholine gic will esul in a leas as good a esponse in lung unc ion pa ame e s wi hou a isk o an icho- line gic ad e se e ec s. Thus, i a pa ien is using a long-ac - ing an icholine gic, he escue medica ion should be a sho - ac ing b 2 -agonis [84]. A e he inaliza ion o he Finnish guideline [2,8,9], wo ixed-dose combina ions o a long-ac ing b 2 -agonis and a long-ac ing an icholine gic ha e been app o ed o be used in he ea men o COPD, namely indaca e ol–glycopy onium and ilan e ol–umeclidinium. In mos s udies, bo h o hese ixed combina ions ha e been shown o imp o e lung unc ion (e.g. ough FEV 1 ) and heal h s a us and o educe dyspnoea be e han he single monocomponen s alone in pa ien s wi h mode a e- o-se e e COPD wi h no appa en sa e y conce ns [64,85–89]. In addi ion, he ixed-dose combina ion o indaca- e ol–glycopy onium has been epo ed o educe mode a e- o-se e e COPD exace ba ions be e han glycopy onium alone [90]. Inhaled glucoco icoids. In he ea men o as hma, he he apeu ic and ad e se e ec s o ICS depend on he dose used [91]. Ins ead, in he ea men o COPD, he dose dependency o he he apeu ic and ad e se e ec s o ICS is no known [92,93]. In long- e m ials, only mode a e and high doses o ICS ha e been used [92,93]. Reg- ula long- e m (>6 mon hs) he apy wi h ICS in COPD educes exace ba ions and slows down he decline in he qual- i y o li e [93]. Gene ally, pa ien s wi h mild disease and wi h- ou p e ious exace ba ion his o y do no bene i om ICS [3,93]. The esponse o ICS in COPD canno be o e old om he esponse o o al glucoco icoids o by measu ing hype - eac i i y o esponse o b onchodila o s (b onchodila o es in spi ome y) [93]. Discon inua ion o ICS may p ecipi a e exace ba ion o he disease in some pa ien s wi h COPD [94] bu may be sa ely pe o med in o he s o dec ease isk o long- e m ad e se e ec s [95]. ICS alone do no a ec mo al- i y due o COPD o he a e o decline o lung unc ion (annual FEV 1 decline) [93]. Ad e se e ec s include candida in ec ion in he mou h and hoa seness. Also, he e is e idence ha use o ICS is associa ed wi h an inc eased isk o pneu- monia [93] and ac u es [96]. Ini ia ion o ICS he apy has been associa ed wi h inc eased isk o diabe es in espi a o y Table 5. The p inciples o combining d ugs used o ea ch onic obs uc i e pulmona y disease (COPD). The gene al ule o d ug he apy o COPD is ha wo d ugs belonging o he same g oup o ha ing simila mechanism o ac ion should no be combined. The excep ion o his ule is he simul a- neous use o sho - and long-ac ing b 2 -agonis s ha is allowed and o en is meaning ul. I he e is a clinical indica ion o combine d ugs om he ollowing g oups, he e is no pha macological eason o p e en he combina ion. To a single pa ien , only one compound o p oduc can be selec ed om he ollowing g oups o d ugs Sho -ac ing b onchodila o s (‘ elie e medica ion’) 1 Sho -ac ing b 2 -agonis ( eno e ol, salbu amol, e bu aline) Sho -ac ing an icholine gic (ip a opium) 2 Long-ac ing b onchodila o s 1 Long-ac ing b 2 -agonis ( o mo e ol, indaca e ol, oloda e ol, salme e ol, ilan e ol) Long-ac ing an icholine gic (aclidinium, glycopy onium, io opium, umeclidinium) 2 Glucoco icoids Inhaled glucoco icoids (beclome hasone, budesonide, lu icasone, mome asone, ciclesonide) O al medica ions Phosphodies e ase 4 inhibi o s ( o lumilas ) 3 Theophylline 3 1 The du a ion o ac ion o he compound does no p e en he combina ion. Fo example, wo long-ac ing b onchodila o s can be combined as long as hey ha e a di e en mechanism o ac ion (i.e. io opium and indaca e ol can be combined). Simila ly, sho -ac ing an icholine gic (ip a opium) can be combined wi h sho -ac ing b 2 -agonis (e.g. salbu amol). Ins ead, wo di e en b 2 -agonis s wi h simila du a ion o ac ion should no be combined (e.g. indaca e ol should no be combined wi h o mo e ol o salme e ol). Use o a sho -ac ing b 2 -agonis as needed wi h a egula long- ac ing b 2 -agonis is accep able. 2 Use o sho -ac ing an icholine gic (ip a opium) wi h long-ac ing an icholine gic is no ecommended. 3 Phosphodies e ase 4 inhibi o s and heophylline should no be combined because o he isk o ad e se e ec s. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). 298 HANNU KANKAANRANTA ET AL. MiniRe iew pa ien s in gene al in a egis y-based s udy [97], bu in a e - ospec i e analysis o sho e placebo-con olled, double-blind s udies in pa ien s wi h as hma o COPD, i has no been con- i med [98]. Long- e m he apy wi h ICS in addi ion o o he he apy is ecommended only o pa ien s wi h ACOS o pa ien s wi h a high isk o exace ba ions o COPD, ha is wi h se e e o e y se e e obs uc ion in spi ome y ( able 2) and a his o y o equen exace ba ions ( ig. 2) [99]. The use o ICS as he sole long- e m he apy o COPD should be a oided as he combina ion o inhaled glucoco icoid wi h long-ac ing b 2 - agonis is mo e e icien in educing exace ba ions o he dis- ease and possibly be e in educing mo ali y and imp o ing lung unc ion and quali y o li e [100]. The use o ICS ou side he cu en indica ions is no ecommended as long- e m he - apy wi h hese may inc ease he isk o pneumonia [92,93], os eopo osis and ac u es [96]. Combina ion o inhaled glucoco icoid and long-ac ing b 2 -agonis . In COPD, he cu en indica ion o he use o di e en ixed combina ions o ICS and long-ac ing b 2 -agonis is equen exace ba ions despi e he use o app op ia e b onchodila o he apy, bu he accep ed FEV 1 anges om <50% p edic ed (budesonide– o mo e ol, beclome hasone dip opiona e– o mo- e ol) o <60% p edic ed ( lu icasone p opiona e–salme e ol) and o <70% p edic ed ( lu icasone u oa e– ilan e ol). The combina ion o inhaled glucoco icoid and a long-ac ing b 2 - agonis educes exace ba ions and imp o es lung unc ion and quali y o li e in COPD (A) [101]. In addi ion, combina ion o inhaled glucoco icoid and a long-ac ing b 2 -agonis is be e han placebo o any o i s componen s in imp o ing lung unc- ion and heal h s a us and educing exace ba ions in pa ien s wi h COPD [100,102–105]. In a la ge, p ospec i e 3-yea ial wi h a combina ion o inhaled glucoco icoid and a long-ac ing b 2 -agonis , he e was no s a is ically signi ican e ec on mo - ali y [106]. Howe e , in a subsequen me a-analysis, i was ound ha a combina ion o inhaled glucoco icoid and a long-ac ing b 2 -agonis may educe mo ali y (numbe needed o ea NNT =36 o p e en one ex a dea h; 95% CI 21; 258) [104]. The use o a combina ion o an inhaled glucoco icoid and a long-ac ing b 2 -agonis is associa ed wi h ad e se e ec s yp- ical o bo h i s componen s. The inc eased isk o pneumonia is conside ed as he mos signi ican in pa ien s wi h COPD [99,104]. A p esen , i emains unce ain o wha ex en inc eased isk o pneumonia is associa ed wi h o he ICS o combina ions o ICS and long-ac ing b 2 -agonis s, bu a combi- na ion o inhaled lu icasone p opiona e and salme e ol may cause a highe isk [107–110]. E en hough COPD is la gely an unde -diagnosed and unde - ea ed disease [3], o e - ea men o mild- o-mode a e COPD (spi ome ic GOLD classi ica ion; able 2) wi h combi- na ions o ICS and long-ac ing b 2 -agonis s was ecen ly epo ed [111]. This canno be ecommended and leads o unnecessa y ad e se e ec s and cos s [111]. Addi ion o a combina ion o an inhaled glucoco icoid and a long-ac ing b 2 -agonis o io opium he apy has been epo ed o imp o e lung unc ion and he quali y o li e, and i may e en u he educe he occu ence o exace ba ions, pa icula ly se e e exace ba ions [112–115], bu mo e and longe s udies a e needed. P elimina y e idence sugges s ha he iple he apy is cos -e ec i e in Finland and o he Scandi- na ian coun ies [116]. Ro lumilas . Ro lumilas inhibi s he in lamma o y eac ion associa ed wi h COPD by inhibi ing enzyme phosphodies e ase 4 (PDE4) and by inc easing in acellula cyclic adenosine monophospha e (cAMP) con en [57]. Ro lumilas is gi en o ally as one able daily. I is no a b onchodila o and canno be used o elie e acu e b onchial obs uc ion, e en hough du ing long- e m he apy in pa ien s al eady on salme e ol o io opium, o lu- milas u he inc eases FEV 1 by 50–80 ml [57,117–119]. Ro lumilas educes exace ba ions o COPD and imp o es lung unc ion, bu i also has signi ican ad e se e ec s (A) [117]. Ro lumilas educes mode a e ( equi ing sys emic glucoco icoids) and se e e (leading o hospi aliza ion o dea h) exace ba ions in pa ien s wi h COPD who ha e se e e COPD (FEV 1 <50% p edic ed), ch onic b onchi is and e- quen exace ba ions despi e long-ac ing b onchodila o s [57,117,118]. In con as , he e ec s on he quali y o li e and symp oms a e less p onounced [57,117]. Typical ad e se e ec s o o lumilas a e gas oin es inal complain s and headache. Weigh loss is also common, and he weigh should be ollowed [117,118]. O he pha macological ea men s used o long- e m he apy. O al glucoco icoids. A ea men ial wi h o al glucoco - icoids is no ecommended in pa ien s wi h COPD o iden i y hose who will espond o ICS. A esponse o o al glucoco icoids has no been shown o p edic he esponse o o he ea men s [23–27]. Howe e , his does no p e en us om ea ing exace ba ions wi h a cou se o o al s e oids o ying a cou se o o al s e oids in a pa ien wi h di icul symp oms. E en hough a high dose (equalling ≥30 mg o al p edniso- lone pe day) o o al glucoco icoids imp o es lung unc ion in he sho un, he e is no e idence o long- e m bene i s o o al glucoco icoids a low o mode a e o high doses [120]. In con as , he e is e idence o sugges inc eased isk o ad e se e ec s [120]. Thus, long- e m he apy o COPD wi h o al glucoco icoids should be a oided as i may e en wo sen he long- e m ou come o he pa ien [121]. O al glucoco ic- oids ha e se e al signi ican ad e se e ec s –one o he mos impo an in he ea men o COPD being s e oid myopa hy which p esen s wi h symp oms such as muscula weakness, impai ed physical ac i i y and espi a o y insu iciency in pa ien s wi h e y se e e COPD [122]. Regula long- e m o al glucoco icoid he apy has se e al well-known ad e se e ec s, and hus, i is easy o unde s and ha he e exis no s udies on i s use in he ea men o s able COPD [3]. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). MiniRe iew FINNISH COPD GUIDELINE 299 105 Wedzicha JA, Singh D, Ves bo J, Paggia o PL, Jones PW, Bon- ne -Gonod F e al. Ex a ine beclome hasone/ o mo e ol in se e e COPD pa ien s wi h his o y o exace ba ions. Respi Med 2014;108:1153–62. 106 Cal e ley PMA, Ande son AMA, Fe guson GT, Jenkins C, Jones PW, Ya es JC e al. Salme e ol and lu icasone p opiona e and su i al in ch onic obs uc i e pulmona y disease. N Engl J Med 2007;356:775–89. 107 Rabe KF, Wedzicha JA. Con o e sies in ea men o ch onic obs uc i e pulmona y disease. Lance 2011;378:1038–47. 108 Suissa S, Pa enaude V, Lapi F, E ns P. Inhaled co icos e oids in COPD and he isk o se ious pneumonia. Tho ax 2013;68: 1029–36. 109 Janson C, La sson K, Lisspe s KH, S € allbe g B, S a elis G, Goike H e al. Pneumonia and pneumonia ela ed mo ali y in pa ien s wi h COPD ea ed wi h ixed combina ions o inhaled co icos e oids and long ac ing b2 agonis : obse a- ional ma ched coho s udy (PATHOS). B Med J 2013;346: 3306. 110 Kew KM, Seniuko ich A. Inhaled s e oids and isk o pneumo- nia o ch onic obs uc i e pulmona y disease. Coch ane Da a- base Sys Re 2014;A . No.:CD010115. 111 Whi e P, Tho n oh H, Pinnock H, Geo gopoulou S, Boo h HP. O e ea men o COPD wi h inhaled co icos e oids –implica- ions o sa e y and cos s: c oss-sec ional obse a ional s udy. PLoS ONE 2013;8:e75221. 112 Aa on SD, Vandemheen KL, Fe gusson D, Mal ais F, Bou beau J, Golds ein R e al. Tio opium in combina ion wi h placebo, salme e ol, o lu icasone-salme e ol o ea men o ch onic obs uc i e pulmona y disease: a andomised ial. Ann In e n Med 2007;146:545–55. 113 Wel e T, Mi a i lles M, He nandez P, E iksson G, Pe e son S, Polanowski T e al. E icacy and ole abili y o budesonide/ o - mo e ol added o io opium in pa ien s wi h ch onic obs uc i e pulmona y disease. Am J Respi C i Ca e Med 2009;180:741– 50. 114 Cazzola M, Ando F, San us P, Rugge i P, Di Ma co F, Sanduzzi Ae al. A pilo s udy o assess he e ec s o combining lu ica- sone p opiona e/salme e ol and io opium o he ai low obs uc- ion o pa ien s wi h se e e- o- e y se e e COPD. Pulm Pha macol The 2007;20:556–61. 115 Ka ne C, Ca es CJ. Combina ion inhaled s e oid and long-ac ing be a2-agonis in addi ion o io opium e sus io opium o com- bina ion alone o ch onic obs uc i e pulmona y disease. Coch- ane Da abase Sys Re 2011;3:CD008532. 116 Nielsen R, Kankaan an a H, Bje me L, Lange P, A ne o p S, Hedegaa d M e al. Cos e ec i eness o adding budesonide/ o - mo e ol o io opium in COPD in ou No dic coun ies. Respi Med 2013;107:1709–21. 117 Chong J, Poole P, Leung B, Black PN. Phosphodies e ase 4 inhibi o s o ch onic obs uc i e pulmona y disease. Coch ane Da abase Sys Re 2011;5:CD002309. 118 Cal e ley PMA, Rabe KF, Goeh ing U-M, K is iansen S, Fabb i LM, Ma inez FJ e al. Ro lumilas in symp oma ic ch onic obs uc i e pulmona y disease: wo andomised clinical ials. Lance 2009;374:685–94. 119 Fabb il LM, Cal e ley PMA, Izquie do-Alonso JL, Bundschuh DS, B ose M, Ma inez FJ e al. Ro lumilas in mode a e- o- se e e ch onic obs uc i e pulmona y disease ea ed wi h long- ac ing b onchodila o s: wo andomised clinical ials. Lance 2009;374:695–703. 120 Wal e s JAE, Wal e s EH, Wood-Bake R. O al co icos e oids o s able ch onic obs uc i e pulmona y disease. Coch ane Da a- base Sys Re 2005;3:CD005374. 121 Schols AMWJ, Wesseling G, Kes e ADM, de V ies G, Mos e R, Slangen J e al. Dose dependen inc eased mo ali y isk in COPD pa ien s ea ed wi h o al glucoco icoids. Eu Respi J 2001;17:337–42. 122 Man WD-C, Kemp P, Moxham J, Polkey MI. Skele al muscle dys unc ion in COPD: clinical and labo a o y obse a ions. Clin Sci (Lond) 2009;117:251–64. 123 Ba nes PJ. Theophylline. Am J Respi C i Ca e Med 2013;188:901–6. 124 Cazzola M, Page CP, Calze a L, Ma e a MG. Pha macology and he apeu ics o b onchodila o s. Pha macol Re 2012;64:450–504. 125 Ram FS, Jones P, Ja dim J, Cas o AA, A allah  AN, Lacasse Y e al. O al heophylline o ch onic obs uc i e pulmona y dis- ease. Coch ane Da abase Sys Re 2002;3:CD003902. 126 Rossi A, K is u ek P, Le ine BE, Thomson MH, Till D, Ko akis Je al. Compa ison o he e icacy, ole abili y, and sa e y o o mo e ol d y powde and o al, slow- elease heophylline in he ea men o COPD. Ches 2002;121:1058–69. 127 Zhou Y, Wang X, Zeng X, Qiu R, Xie J, Liu S e al. Posi i e bene i s o heophylline in a andomized, double-blind, pa allel- g oup, placebo-con olled s udy o low-dose, slow- elease he- ophylline in he ea men o COPD o 1 yea . Respi ology 2006;11:603–10. 128 ZuWallack RL, Mahle DA, Reilly D, Chu ch N, Emme A, Ricka d K e al. Salme e ol plus heophylline combina ion he - apy in he ea men o COPD. Ches 2001;119:1661–70. 129 Leh im€ aki L, Saano V, Moilanen E. Hengi yselimis € o€ on aiku a- a l€ a€ akeainee [D ugs a ec ing espi a o y sys em]. In: Pelkonen O, Ruskoaho H, Hakkola J, Huupponen R, MacDonald E, Moi- lanen E, Pasanen M, Scheinin M, V€ ah€ akangas K (ed.). L€ a€ ake i- e eellinen a makologia ja oksikologia [Medical Pha macology and Toxicology]. Kus annus Oy Duodecim, Helsinki, Finland, 2014;733–56. 130 Dona h E, Chaudh y A, He nandez-Aya LF, Li L. A me a- analysis on he p ophylac ic use o mac olide an ibio ics o he p e en ion o disease exace ba ions in pa ien s wi h ch onic obs uc i e pulmona y disease. Respi Med 2013;107:1385–92. 131 Albe RK, Conne J, Bailey WC, Casabu i R, Coope JAD J , C ine GJ e al. Azi h omycin o p e en ion o exace ba ions o COPD. N Engl J Med 2011;365:689–98. 132 Poole P, Black PN, Ca es CJ. Mucoly ic agen s o ch onic b on- chi is o ch onic obs uc i e pulmona y disease. Coch ane Da a- base Sys Re 2012;8:CD001287. 133 Yawn BP, Colice GL, Hodde R. P ac ical aspec s o inhale use in he managemen o ch onic obs uc i e pulmona y disease in he p ima y ca e se ing. In J Ch on Obs uc Pulmon Dis 2012;7:495–502. 134 Laube BL, Janssens HM, de Jongh FH, De adason SG, Dhand R, Dio P e al. Wha he pulmona y specialis should know abou he new inhala ion he apies. Eu Respi J 2011;37:1308–31. 135 Wieshamme S, D eyhaup J. D y powde inhale s: which ac o s de e mine he equency o handling e o s? Respi a ion 2008;75:18–25. 136 Chapman KR, Voshaa TH, Vi chow JC. Inhale choice in p i- ma y p ac ice. Eu Respi Re 2005;14:117–22. 137 Ba RG, Bou beau J, Cama go CA J . Tio opium o s able ch onic obs uc i e pulmona y disease. Coch ane Da abase Sys Re 2005;2:CD002876. 138 Lange P, Ma o JL, Ves bo J, Olsen KR, Ingeb ig sen TS, Dahl Me al. P edic ion o he clinical cou se o ch onic obs uc i e pulmona y disease, using he new GOLD classi ica ion. A s udy o he gene al popula ion. Am J Respi C i Ca e Med 2012;186:975–81. 139 Wedzicha JA, Cal e ley PMA, Seemungal TA, Hagan G, Ansa i Z, S ockley RA e al. The p e en ion o ch onic obs uc i e pul- mona y disease exace ba ions by salme e ol/ lu icasone p opio- na e o io opium b omide. Am J Respi C i Ca e Med 2008;177:19–26. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). 306 HANNU KANKAANRANTA ET AL. MiniRe iew 140 Apple on S, Poole P, Smi h BJ, Veale A, Lasse son TJ, Chan MMK e al. Long-ac ing be a2-agonis s o poo ly e e sible ch onic obs uc i e pulmona y disease. Coch ane Da abase Sys Re 2006;3:CD001104. 141 Ma che i N, C ine GJ, Albe RK. P e en ing acu e exace ba- ions and hospi al admissions in COPD. Ches 2013;143:1444– 54. 142 Pi as B, Mi a i lles M. The o e lap pheno ype: he (missing) link be ween as hma and COPD. Mul idiscip Respi Med 2012;7:8. 143 Ca olan BJ, Su he land ER. Clinical pheno ypes o ch onic obs uc i e pulmona y disease and as hma: ecen ad ances. J Alle gy Clin Immunol 2013;131:627–34. 144 Louie S, Zeki AA, Schi o M, Chan AL, Yoneda KY, A dalo ic Me al. The as hma-ch onic obs uc i e pulmona y disease o e - lap synd ome: pha maco he apeu ic conside a ions. Expe Re Clin Pha macol 2013;6:197–219. 145 Magnussen H, Bugnas B, an Noo d J, Schmid P, Ge ken F, Kes en S. Imp o emen s wi h io opium in COPD pa ien s wi h concomi an as hma. Respi Med 2008;102:50–6. 146 Koblizek V, Chlumsky J, Zind V, Neumanno a K, Za loukal J, Zak J e al. Ch onic obs uc i e pulmona y disease: o icial diagnosis and ea men guidelines o he Czech Pneumological and Ph hisiological Socie y; a no el pheno ypic app oach o COPD wi h pa ien -o ien ed ca e. Biomed Pap Med Fac Uni Palacky Olomouc Czech Repub 2013;157:189–201. 147 Russi EW, Ka e W, B u sche M, Eich C, Fi ing JW, F ey M e al. Diagnosis and managemen o ch onic obs uc i e pulmo- na y disease: he Swiss guidelines. O icial guideline o he Swiss espi a o y socie y. Respi a ion 2013;85:160–74. ©2014 The Au ho s. Basic & Clinical Pha macology & Toxicology published by John Wiley & Sons L d on behal o No dic Associa ion o he Publica ion o BCPT ( o me No dic Pha macological Socie y). MiniRe iew FINNISH COPD GUIDELINE 307