Pharmacological treatment of COPD : new evidence

Pulmonol. 2019;25(2):90---96 www.jou nalpulmonology.o g REVIEW Pha macological ea men o COPD --- New e idence N. Pi esa, P. Pin ob,c, N. Ma c¸al d, A.J. Fe ei ae, , C. Rod iguesg, C. Bá ba ab,c,∗, on behal o GI DPOC --- In e es G oup on Ch onic Obs uc i e Pulmona y Disease aPulmonology Depa men , Hospi al San a Ma ia Maio , Ba celos, Po ugal bChes Depa men , Cen o Hospi ala Lisboa No e, Lisbon, Po ugal cEn i onmen al Heal h Ins i u e (ISAMB), Facul y o Medicine, Uni e si y o Lisbon, Po ugal dPulmonology Depa men , Hospi al de Vila F anca de Xi a, Po ugal ePulmonology Depa men , Cen o Hospi ala Uni e si á io de Coimb a, Po ugal Facul y o Medicine, Uni e si y o Coimb a, Po ugal gCen o Hospi ala de Coimb a, Po ugal Recei ed 13 Sep embe 2018; accep ed 14 Oc obe 2018 KEYWORDS FLAME; P e-GOLD pa ien s; Diagnosis; Algo i hm Abs ac Ch onic Obs uc i e Pulmona y Disease (COPD) is cu en ly he 4 h leading cause o dea h wo ldwide bu is p ojec ed o be he 3 d leading cause o dea h by 2020. In Po ugal, he es ima ed p e alence o COPD in he Lisbon egion is 14.2%, and a la ge p opo ion o unde diagnosed disease has been de ec ed. In 2016, a Po uguese panel o expe s p oposed pha macological ea men app oaches o COPD based on he e idence a ailable a he ime. Howe e , gi en ha he GOLD 2017 epo in oduced conside able changes o he 2016 e sion, and ha new e idence has eme ged ega ding ea men op ions, hese p oposals need o be upda ed. Also, and based on se e al s udies, he concep o P e-GOLD pa ien s, which has diagnos ic, p ognos ic and he apeu ic implica ions, is in oduced, along wi h a p oposed algo i hm o he iden ifica ion and ea men o hese pa ien s. © 2019 Sociedade Po uguesa de Pneumologia. Published by Else ie Espa˜ na, S.L.U. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by- nc-nd/4.0/). ∗Co esponding au ho . E-mail add ess: [email p o ec ed] (C. Bá ba a). In oduc ion Ch onic Obs uc i e Pulmona y Disease (COPD) is cu en ly he 4 h leading cause o dea h wo ldwide bu is p ojec ed o be he 3 d leading cause o dea h by 2020.1In Po ugal, he es ima ed p e alence o COPD in he Lisbon egion is 14.2%, h ps://doi.o g/10.1016/j.pulmoe.2018.10.005 2531-0437/© 2019 Sociedade Po uguesa de Pneumologia. Published by Else ie Espa˜ na, S.L.U. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Pha macological ea men o COPD - New e idence 91 and a la ge p opo ion o unde diagnosed disease has been de ec ed.2 In 2016, a Po uguese panel o expe s p oposed pha - macological ea men app oaches o COPD based on he e idence a ailable a he ime.3Howe e , he GOLD 2017 epo 4in oduced conside able changes o he 2016 e sion.5Acco ding o he 2017 s a egy, COPD pa ien s con inue o be sepa a ed in o A, B, C o D acco ding o symp oms and exace ba ions. Howe e , p e ious GOLD epo s s a ified pa ien s conside ing h ee isk a iables --- o ced expi a o y olume in 1 second (FEV1), symp oms and exace ba ions.5The implica ions o hese changes a e ha pa ien s who we e p e iously conside ed a isk due o poo lung unc ion only (C o D), will now be classified as A o B, espec i ely, wi h epe cussions in he he apeu ic s a egy ecommended. The mos ecen GOLD 20181did no in oduce changes o he GOLD 2017 classifica ion.4 Also, he FLAME s udy6 --- 8 p o ided new e idence ega d- ing ea men op ions o B and D pa ien s, showing ha indaca e ol/glycopy onium was mo e e ec i e han salme e ol/flu icasone in educing and p e en ing COPD exace ba ions in pa ien s wi h a his o y o exace ba ions du ing he p e ious yea , and ha his e ficacy was inde- penden o di e en cu o s o baseline blood eosinophilia. Finally, and based on se e al s udies,9---13 he concep o P e-GOLD pa ien s, which has diagnos ic, p ognos ic and he apeu ic implica ions, is in oduced, along wi h a p o- posed algo i hm o he iden ifica ion and ea men o hese pa ien s. P e-GOLD pa ien s The diagnosis o COPD equi es a a io o FEV1 o o ced i al capaci y (FVC) o less han 0.70 as assessed by spi ome y a e b onchodila o use.4Howe e , a ecen s udy epo ed ha 50% o smoke s wi h p ese ed pulmona y unc ion ha e espi a o y symp oms, including exace ba ions, limi a ion o ac i i y, and g ea e ai way-wall hickening wi hou emphysema. Among symp oma ic cu en o o me smoke s, 42% used b onchodila o s and 23% used inhaled glucoco icoids, wi hou any e idence base.9This s udy con- fi med p e ious findings epo ing ha he e ec o ch onic smoking on he lungs is subs an ially unde es ima ed i jus spi ome y is used.10 In ac , pos -salbu amol FEV1change is simila in pa ien s wi h COPD and smoking con ols11; a significan p opo ion o smoke s wi h emphysema bu wi hou ai way limi a ion had al e a ions in hei quali y o li e, numbe o exace ba ions and di using capaci y o he lungs o ca bon monoxide (DLCO) alues.12 Taken oge he , all hese s udies confi m ha FEV1is an un eliable measu e o symp om bu den and exace ba ions in smoke s, bu lea e a gap on how o ea hese pa ien s in o de o educe symp oms and p e en exace ba ions.13 We p opose a diag- nos ic and ea men algo i hm o e alua e and medica e hese pa ien s --- Fig. 1. E e y smoke o o me smoke wi h symp oms and exace ba ions should unde go spi ome y. I spi ome y, pos -b onchodila o FEV1/FVC < 0.70, alues a e consis en wi h he GOLD 2018 c i e ia o COPD, he pa ien should be ea ed acco dingly. I he alue o FEV1/FVC is be ween 0.6 and 0.8, spi ome y should be epea ed on a sepa a e occasion,1since his a io may change as a esul o biological a ia ion.14,15 I he ini ial FEV1/FVC a io is less han 0.6 i is e y unlikely ha i will ise abo e 0.7 spon aneously.15 I spi ome y alues a e no in acco dance wi h he GOLD 2018 c i e ia o COPD, and symp oms and exace ba ions con inue o pe sis , he pa ien should be checked o occul ai flow obs uc ion using he Lowe Limi o No mal (LLN) ange.16 I he LLN is achie ed, he pa ien should be diagnosed wi h COPD and ea ed acco ding o GOLD 2018.1I no , and symp oms and exace ba ions con inue o pe sis , a comple e assessmen should be done, including a ho acic Compu e ized Tomog aphy (CT) scan o he di e en ial diagnosis o emphysema, cance and o he lung pa hologies. Rega dless o whe he he CT scan is posi i e o nega i e o emphysema/ai way-wall hickening, he pa ien should unde go a ial wi h a b onchodila o and be e-assessed 3 --- 6 mon hs la e . This concep o p e-GOLD pa ien s we he e in oduce is e y simila o ha ecen ly p oposed by Celli and Agus i.17 In hei wo k, he au ho s a gue ha indi iduals who ha e symp oms simila o hose o pa ien s wi h COPD (namely, dyspnea, cough and/o spu um p oduc ion) and s uc u al lung abno mali ies bu wi hou pe sis en ai flow limi a- ion may be classified as ‘‘P e-COPDs’’. The ‘‘P e-COPDs’’ idea has wide implica ions han ou p e-GOLD concep , as, acco ding o hose au ho s, no pas o cu en exposu e o ciga e e smoke is equi ed. GOLD A pa ien s GOLD 2017/2018 clea ly s a e ha he goals o ea men o s able COPD a e o educe symp oms and isk, by imp o - ing exe cise ole ance and heal h s a us and p e en ing disease p og ession, exace ba ions and mo ali y.1,4 Resul s om a la ge ecen s udy show ha exace ba ions accele - a e lung unc ion loss in subjec s wi h es ablished COPD, pa icula ly when hey a e se e e and occu in pa ien s wi h mild disease.18 This is no su p ising since pa ien s wi h mild disease ha e be e lung unc ion and he e o e mo e o lose. Also, wo ecen expe e iews sugges ha mo e agg essi e ea men s should be implemen ed in he ea lie s ages o COPD,19 in o de o slow disease p og es- sion and imp o e Quali y o Li e (QoL),20 hus ob aining he bes possible ou come.19 Cu en da a suppo main enance ea men wi h a long-ac ing b onchodila o in his pa ien g oup.20 Gi en he abo e, he a ionale o ch onic he - apy o GOLD A pa ien s is o p e en exace ba ions and slow disease p og ession. The GOLD 2016 epo p oposed sho ac ing be a agonis s (SABA) o sho ac ing musca inic an agonis s (SAMA) as fi s choice he apy in hese pa ien s, wi h long ac ing be a agonis s (LABA) o long ac ing mus- ca inic an agonis s (LAMA) o SABA/SAMA as he al e na i e choice.5Be o e he GOLD 2017 epo was published, one expe opinion pape p oposed a SABA o SAMA when pos - b onchodila o FEV1/FVC < 0.70 wi h occasional dyspnea and a LABA o LAMA when dyspnea is pe sis en ,21 and ano he expe p oposed he di ision o GOLD A pa ien s in o wo sub-g oups: pa ien s wi h FEV1> 80% and wi h no wo sening o FEV1in he annual assessmen should be ea ed wi h a SABA o SAMA only in SOS, and pa ien s wi h 50% < FEV1< 80% and/o wo sening o FEV1in he annual assessmen should be ea ed wi h a LABA o LAMA.3Howe e , acco ding o 92 N. Pi es e al. SMOKER o FORMER SMOKER + SYMPTOMS and/o EX ACER BATIONS SPIROMET RY GOLD 2018 COPD C i e ia GOLD 2018 COPD C i e ia Pha macological ea men Pe sis en symp oms and/o exace ba ions COPDChes CT and PFT comple ed wi h DLCO Pe sis en symp oms and/o exace ba ions Emphysema o wall hickness TRIAL THERAPY wi h b onchodila o and e-assessmen a e 3-6 mon hs Repea 1x *< lowe limi o no mal = < 5 h pe cen ile Figu e 1 P oposed diagnos ic and ea men algo i hm o e alua e and medica e p e-GOLD pa ien s. he GOLD 2017 epo ,4FEV1should no longe guide ea - men , bu symp oms and exace ba ion isk ins ead, and as such, ecommenda ions o hese pa ien s a e ei he a sho - o a long-ac ing b onchodila o , which can be swi ched o ano he class o b onchodila o i he e is no symp om elie , and con inued o discon inued depending on symp- oma ic benefi . The e o e, gi en ha he cu en goals o main enance he apy a e o educe symp oms and p e en exace ba ions, hen a LABA should be chosen o he o me (symp oms educ ion),22 and a LAMA o he la e (exace - ba ions p e en ion) since i has been epo ed o be supe io o LABA ega ding exace ba ion p e en ion.23,24 Dual b on- chodila ion wi h LABA/LAMA should no be o e ed o hese pa ien s because hey a e nei he equen exace ba o s no e y symp oma ic. I is wo h no ing ha , depending on he ins umen used o he classifica ion o symp oms, he modified Medical Resea ch Council scale (mMRC) o he COPD assessmen es (CAT), a pa ien may be classified as A o B25,26 and he e o e bo h ins umen s a e ecommended. We p opose ha ch onic main enance he apy wi h a LABA o a LAMA should be o e ed o GOLD A pa ien s. We ag ee wi h GOLD 2018 in ha a swi ch o ano he class o b onchodila o can be made i he e is no symp om elie , and he apy should be con inued o discon inued depending on symp oma ic benefi . GOLD B pa ien s Al hough inhaled co icos e oids (ICS) a e no ecommended as main enance he apy o GOLD B pa ien s,3,5,21,27 eal- wo ld s udies o baseline cha ac e is ics o pa ien s en olled in RCTs show ha up o 51.8% o hese pa ien s a e s ill medica ed wi h ICS.28---33 In a pape om 2016, we specu- la ed ha his was mainly due o he gene alized idea ha a pa ien aking ICS will be mo e con olled han a pa ien who is no on ICS he apy, and will no exace ba e o de e io- a e, which is no ue.3Ou specula ion is now suppo ed by e idence om he FLAME s udy, ha andomized a o al o 1680 pa ien s o he indaca e ol/glycopy onium 110/50 ␮g once-daily g oup and 1682 o he salme e ol/flu icasone 50/500 ␮g wice-daily g oup, and showed ha o GOLD B pa ien s wi h a his o y o a leas one exace ba ion du ing he p e ious yea , indaca e ol/glycopy onium was mo e e ec i e han salme e ol/flu icasone in p e en ing COPD exace ba ions, i espec i e o p io ICS/LABA/LAMA he apy,7and was associa ed wi h no de ec able inc ease Pha macological ea men o COPD - New e idence 93 Table 1 p oposed di ision o GOLD B pa ien s in wo subg oups and espec i e he apeu ic app oaches. Sub-g oup cha ac e is ics The apeu ic app oach BX1: mMRC = 2 AND 0 exace ba ions; AND no ca dio ascula co-mo bidi ies (a) i no medica ed, ini ia e LABA o LAMA BX2: mMRC > 2 OR 1 exace ba ion wi hou hospi aliza ion OR wi h ca dio ascula co-mo bidi ies LABA + LAMA (‘‘hi ha d’’ app oach) mMRC --- modified Medical Resea ch Council dyspnea scale; LABA --- long ac ing ␤2-agonis ; LAMA --- long-ac ing musca inic an agonis . in ad e se e en s.6The FLAME s udy also suppo s ou p e ious ecommenda ion ha B pa ien s wi hou exace - ba ions, who a e o e ea ed wi h ICS, should be wi hd awn om ICS,3and u he sugges s ha e en B pa ien s wi h a leas one exace ba ion du ing he p e ious yea can and should be wi hd awn om ICS.6,7 Symp oma ic pa ien s a e mo e likely o expe ience exace ba ions34 ( he ECLIPSE s udy showed ha 52% o hese pa ien s a e exace ba o s),35 and he e o e i is o he u mos impo ance o con ol symp oms, namely wi h dual b onchodila ion,3,21,27 which is now clea ly suppo ed by he FLAME s udy and o he s udies om he IGNITE clinical de elopmen p og am o indaca e ol/glycopy onium.6,7,36,37 In he Sal o d Lung S udy, a la ge andomized open-label ial designed o mimic eal-wo ld condi ions, a once-daily ea men egi- men o combined flu icasone u oa e/ ilan e ol 100/25 ␮g was compa ed o usual ca e, and he au ho s concluded ha he flu icasone u oa e/ ilan e ol combina ion was associ- a ed wi h a lowe a e o exace ba ions han usual ca e, wi hou a g ea e isk o se ious ad e se e en s.38 I is ou opinion ha his s udy does no con adic he FLAME s udy o se e al easons: in he Sal o d Lung S udy38 22% o he pa ien s included had a diagnosis o as hma, he com- pa a o a m was usual ca e as de e mined by he gene al p ac i ione , which esul ed in a a ie y o mono he apies and/o combina ion he apies (88% o pa ien s in he usual ca e g oup we e ecei ing an ICS-con aining egimen), and unila e al c osso e was pe mi ed. The e o e, he conclu- sions d awn by he au ho s ha e se e al possible sou ces o bias and i is no possible o conclude om hese da a whe he flu icasone and ilan e ol is mo e e ec i e han a LABA/LAMA a educing exace ba ions. The ECLIPSE35 and FLAME6,7 s udies g ouped pa ien s acco ding o he GOLD 2016 epo 5 hus including FEV1as a isk c i e ion. F om GOLD 2017 onwa ds1,4 FEV1is no longe a c i e ion o isk, only symp oms and exace ba ions. The FLAME s udy s a es ha 19.3% o pa ien s had ≥2 exace ba- ions, and hese will now be he GOLD D pa ien s; as o he emaining pa ien s in ol ed in he s udy, hose wi h ≤1 exac- e ba ion wi hou hospi aliza ion, will be now classified as GOLD B. In ac , since he GOLD 2017 classifica ion,1,4 i is o be expec ed ha many pa ien s o me ly classified as GOLD D would now be classified as GOLD B, because hey we e classified as GOLD D due o FEV1. These GOLD B pa ien s a e he mos he e ogeneous and uns able, and may e en ually exace ba e.35 Thus, he conclusions o he FLAME s udy hold ue ega dless o he GOLD s a ifica ion. Howe e , wi h his new classifica ion, and as many o - me GOLD D pa ien s will now be conside ed GOLD B, hey a e p obably on ICS he apy, as ecommended o GOLD D pa ien s. These pa ien s, p e iously classified as GOLD D due o FEV1and no due o exace ba ions, should be wi hd awn om ICS. In a p e ious pape we p oposed ha GOLD B pa ien s should be di ided in wo subg oups, BX1 and BX2, and he he apeu ic app oach should be based on his subdi ision.3 Since GOLD 2017 led o changes in COPD pa ien classifica- ion, in his pape we ha e adap ed, ou p oposal as shown in Table 1. We p opose ha ICS should no be gi en o GOLD B pa ien s as main enance he apy. We u he p opose ha p e iously GOLD D pa ien s now conside ed GOLD B pos GOLD 2017 and who a e on ICS he apy should be wi hd awn om i , and be moni o ed 3 --- 6 mon hs la e .3 GOLD C pa ien s Acco ding o he 2017/2018 GOLD C new classifica ion,1,4 he g oups C1 (high isk due o poo lung unc ion) and C3 (high isk due o bo h poo unc ion and exace ba ions)3no longe exis and all GOLD C pa ien s will be classified as high isk based only on exace ba ions. The e o e, he main he apeu- ic goal will be o educe he isk o exace ba ions. As ini ial he apy should consis o a single long ac ing b onchodila- o , a LAMA should be p e e ed o a LABA since i has been epo ed o be be e a p e en ing exace ba ions.23,24 We ag ee wi h GOLD 2018 ha hese pa ien s should s a he apy wi h jus LAMA and hen, i exace ba ions con inue, should p e e ably be swi ched o LABA/LAMA, ins ead o LABA/ICS, al hough he la e emains an op ion. GOLD D pa ien s How o s a he apy Many guidelines ha e ecommended LABA/ICS and/o LAMA as fi s -line he apy o highe isk pa ien s.3,5 Howe e , some disc epancies exis , and he he apy app oach o hese pa ien s is no s aigh o wa d.3,21,27,33 A me a-analysis om 2015 concluded ha LAMA/LABA seemed o be a be e op ion o ea ing GOLD D pa ien s (as defined p e-GOLD 2017/2018) han LABA/ICS.39 The FLAME s udy suppo s his conclusion, a o ing indaca e ol/glycopy onium e - sus salme e ol/flu icasone in p e en ing exace ba ions in GOLD D pa ien s (as defined p e-GOLD 2017/2018),6includ- ing pa ien s wi h p io iple he apy.7When compa ed wi h salme e ol/flu icasone, indaca e ol/glycopy onium was be e a p e en ing all exace ba ions and delaying he ime o fi s exace ba ion, any exace ba ion (p < 0.001), mode a e- o-se e e exace ba ions (p < 0.001) and se e e 94 N. Pi es e al. exace ba ions (p = 0.046). The imp o emen o e ime in he o al sco e on he S . Geo ge’s Respi a o y Ques ion- nai e o COPD pa ien s (SGRQ-C) was significan ly g ea e han salme e ol/flu icasone a e day 85. Also, a week 52, he pe cen age o pa ien s who had a clinically impo - an dec ease o a leas 4 poin s in he o al sco e on he SGRQ-C was significan ly highe and he use o escue medica ion was significan ly imp o ed o he pa ien s in he indaca e ol/glycopy onium ea men a m e sus hose in he salme e ol/flu icasone a m. On subg oup analysis, he ad an age o indaca e ol/glycopy onium was pa ic- ula ly ele an o cu en smoke s, pa ien s wi h se e e ai flow limi a ion, GOLD D pa ien s, pa ien s wi h 1 exac- e ba ion in he p e ious yea , and p e ious use o LABA o LAMA. As o ad e se e en s, indaca e ol/glycopy onium was no associa ed wi h a de ec able inc ease in ad e se e en s and he incidence o pneumonia was significan ly lowe in he indaca e ol/glycopy onium g oup han in he salme e ol/flu icasone g oup (3.2% s 4.8%, p = 0.02). This was also he fi s s udy o p ospec i ely analyze he ele- ance o blood eosinophilia in COPD, and he esul s we e simila o blood eosinophilia < 2% compa ed o ≥2%. O he analyses in subg oups defined acco ding o di e en cu - o s o baseline blood eosinophil coun s p o ided simila esul s.6,8 Da a om he fi s head- o-head s udy (TRIBUTE) compa ing a iple combina ion o LABA/LAMA/ICS (beclome asone/ o mo e ol/glycopy onium, 100/6/12.5 ␮g, wo inhala ions wice-daily) wi h a dual combina ion o LABA/LAMA (IND/GLY) ha e jus ecen ly been published.40 The TRIBUTE s udy en olled symp oma ic pa ien s (CAT ≥ 10) wi h a FEV1< 50% and a his o y o a leas one documen ed mode a e o se e e exace ba ion in he pas yea . The p ima y endpoin analysis showed a 15% educ ion in he a e o mode a e o se e e exace ba ions a o ing he iple combina ion when compa ed wi h he dual combina ion (p = 0.043). I should be no ed ha no significan di e ence be ween ea men egimens was obse ed when mode a e and se e e exace ba ions we e analyzed sepa a ely (p = 0.118 and p = 0.189, espec i ely) o o he ime o fi s mode a e o se e e exace ba ion (p = 0.219) and ime o fi s se e e exace ba ion (p = 0.405). In addi ion, he p e-specified subg oup analyses sugges ha pa ien s wi h: FEV1< 30%, o emphysema o a mixed pheno ype, o >1 exace ba ion in he p e ious 12 mon hs, o lowe blood eosinophils (<2% o <200 cells/␮L) may no de i e any benefi om LABA/LAMA/ICS compa ed wi h LABA/LAMA. In e es ingly, he incidence o pneumonia was simila be ween he wo egimens. The esul s om TRIBUTE a e en i ely in line wi h he cu en GOLD ec- ommenda ions and indica e ha pa ien s wi h ch onic b onchi is and ele a ed blood eosinophil coun s will be mo e likely o benefi om a iple combina ion egimen. Recen da a om he IMPACT s udy also appea o be in line wi h he GOLD ecommenda ions wi h iple he apy wi h flu icasone u oa e/umeclidinium/ ilan e ol showing benefi s in pa ien s wi h equen exace ba ions and in hose wi h a se e e exace ba ion in he 12 mon hs p e ious o s udy en ollmen when compa ed wi h flu icasone u oa e/ ilan e ol and umeclidinium/ ilan e ol.41 Despi e his, and as men ioned by Suissa & D azen, in an Edi o ial on he IMPACT s udy42: ‘‘Howe e , he selec ed ial pa ien s, mos o whom we e al eady ea ed wi h inhaled glucoco - icoids and some o whom had a his o y o as hma, we e no he na u al popula ion in which o s udy his ques ion, po en ially a ificially infla ing he obse ed e ec i eness o he iple- he apy inhale o e dual b onchodila o ea men ’’. Consequen ly, he pa ien popula ion in ol ed in he IMPACT s udy makes i e y di ficul o in e p e hese da a and come o a clea conclusion abou i s ele ance o he managemen o COPD pa ien s. In ace o he esul s desc ibed abo e, we ecommend ha GOLD D pa ien s should s a he apy wi h dual b on- chodila ion, and ICS should only be used as an add-on i pa ien s ha e u he exace ba ions. We also p opose ha ICS should no be gi en o hese pa ien s as fi s line main- enance he apy. I and when o add ICS A ecen pos hoc analysis o he WISDOM s udy concluded ha a his o y o ≥2 exace ba ions pe yea plus an eosinophil coun ≥300 cells/␮L iden ifies indi iduals a inc eased isk o exace ba ion when ICS is discon inued. These au ho s epo ha he mos consis en and g ea es e ec was seen in pa ien s wi h ≥2 exace ba ions and ≥400 cells/␮L. Ne e heless, he au ho s ecognize ha , gi en he ela- i ely small sample sizes, mo e s udies a e needed, along wi h p ospec i e confi ma ion o he alidi y o he p o- posed subg oups o ICS- esponsi e indi iduals.43 New da a on his subjec ha e now been p o ided by he SUNSET s udy whe e non- equen ly exace ba ing pa ien s on long- e m iple he apy wi h io opium plus salme e ol/flu icasone we e andomized o ei he con inue hei iple he apy eg- imen o swi ch o indaca e ol/glicopi onium.44 The swi ch o indaca e ol/glycopi onium led o a small educ ion in lung unc ion (-26 mL in ough FEV1) bu no di e ence in COPD exace ba ions be ween ea men g oups. In addi ion, he s udy also demons a es ha pa ien s wi h highe blood eosinophil coun s o ≥300 cells/␮L a e mo e likely o ben- efi om iple he apy as a as loss o lung unc ion is conce ned.44 Due o he lack o mo e conclusi e da a, he ec- ommended ea men app oach is he one p oposed p e iously.3,21,27 Conclusions Based on he GOLD 2017/2018 and on new e idence ha has eme ged ega ding ea men op ions wi h he FLAME s udy, his pape p o ides an upda e on a p e ious p oposal o pha macological ea men app oaches o COPD pa ien s. Also, he concep o P e-GOLD pa ien s, which has diagnos- ic, p ognos ic and he apeu ic implica ions, is in oduced, along wi h a p oposed algo i hm o he iden ifica ion and ea men o hese pa ien s. Financial suppo Funding o his pape was p o ided by No a is Po ugal. Funding was used o access all necessa y scien ific bibliog- aphy and co e mee ings expenses. No a is Po ugal had Pha macological ea men o COPD - New e idence 95 no ole in he collec ion, analysis and in e p e a ion o da a, in he w i ing o he pape and in he decision o submi he pape o publica ion. Conflic s o in e es Nuno Pi es epo s pe sonal ees om No a is. Paula Pin o epo s pe sonal ees om No a is. Nelson Ma c¸al epo s pe sonal ees om No a is, Te a and Boeh inge -Ingelheim. An ónio Jo ge Fe ei a epo s pe sonal ees om No a is, Bial, Boeh inge -Ingelheim, GSK, Tecnin a and Te a. Cidália Rod igues epo s pe sonal ees om No a is. C is ina Bá - ba a has no hing o disclose. Re e ences 1. Global Ini ia i e o Ch onic Obs uc i e Lung Disease. Global s a egy o he diagnosis, managemen and p e en ion o ch onic obs uc i e pulmona y disease; 2018. 2. Ba ba a C, Rod igues F, Dias H, Ca doso J, Almeida J, Ma os MJ, e al. Ch onic obs uc i e pulmona y disease p e alence in Lisbon, Po ugal: he bu den o obs uc i e lung disease s udy. Re Po Pneumol. 2013;19:96---105. 3. 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