In a key Academy of Managed Care Pharmacy (AMCP) Science and Innovation Theater Webinar,

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1 C L I N I C A L B R I E F EDITORIAL & PRODUCTION Senior Clinicl Project Mnger Id Delmendo Clinicl Project Mnger Ted Pigeon Mnging Medicl Writer Angeli Szwed Associte Medicl Writers Elizbeth Kukielk, PhrmD, CGP Monic Trn, PhrmD Project Coordintor Andre Szeszko Assistnt Editors Jillin Pstor Hyley Fhey Copy Chief Jennifer Potsh Copy Editors Mggie Shw Rchelle Lliberte Pul Silvermn Designer Julinne Costello SALES & MARKETING Senior Vice President, Mnged Mrkets Jeff Prescott, PhrmD Director of Sles Gil Hernndez Ntionl Account Mngers Robert Foti Ryn O Lery Ben Bruch Megn Hlsch Clinicl Evidence Supporting the Evolving COPD Tretment Prdigm: Considertions for Mnged Cre nd Evidence-Bsed Recommendtions for Approprite Utiliztion of COPD Tretment Strtegies This publiction ws mde possible through finncil support provided by Boehringer Ingelheim Phrmceuticls, Inc. July 2018 OPERATIONS & FINANCE Circultion Director Jon Severn circultion@mjhssoc.com CORPORATE Chirmn nd CEO Mike Hennessy, Sr Vice Chirmn Jck Lepping President Mike Hennessy, Jr Chief Operting Officer George Gltcz Chief Finncil Officer Neil Glsser, CPA/CFE Vice President, Finnce Leh Bbitz, CPA Controller Ktherine Wyckoff Senior Vice President, Opertions Tom Tolvé Vice President, Editoril Services nd Production Kerrie Keegn Vice President, Digitl Medi Jung Kim Chief Cretive Officer Jeff Brown Director, Humn Resources Shri Lundenberg 2018 Mnged Cre & Helthcre Communictions, LLC Opinions expressed by uthors, contributors, nd dvertisers re their own nd not necessrily those of Mnged Cre & Helthcre Communictions, LLC, the editoril stff, or ny member of the editoril dvisory bord. Mnged Cre & Helthcre Communictions, LLC, is not responsible for ccurcy of dosges given in rticles printed herein. The ppernce of dvertisements in this publiction is not wrrnty, endorsement, or pprovl of the products or services dvertised or of their effectiveness, qulity, or sfety. Mnged Cre & Helthcre Communictions, LLC, disclims responsibility for ny injury to persons or property resulting from ny ides or products referred to in the rticles or dvertisements. In key Acdemy of Mnged Cre Phrmcy (AMCP) Science nd Innovtion Theter Webinr, experts provided insights into the considertions for mnged cre in the evolving chronic obstructive pulmonry disese (COPD) tretment prdigm nd the clinicl evidence supporting the use of dul bronchodiltion with long-cting muscrinic receptor ntgonist (LAMA)/ long-cting bet 2 gonist (LABA) combintion therpies compred with LABA/inhled corticosteroid (ICS) therpies for the mngement of ptients with COPD. A substntil chnge ws introduced in the 2017 Globl Inititive for Chronic Obstructive Lung Disese (GOLD) recommendtions, bsed on high-qulity supporting evidence, which highlighted LABA/LAMA s the preferred combintion tretment over LABA/ICS, nd provided limittions to ICS-contining tretment use in the mngement of COPD. 1 The expert discussion highlighted mnged cre perspectives nd clinicl implictions following the implementtion of this substntil updte in the 2018 GOLD report for the second yer. 2 PREVALENCE AND ECONOMIC BURDEN OF COPD IN THE UNITED STATES The Growing Burden of COPD According to the CDC, n estimted 15.7 million Americns hve been dignosed with COPD. 3 Although COPD is often perceived s disese of the elderly, more thn hlf (67.0%) of ll ptients dignosed with COPD re 64 yers nd younger. 3 COPD is tretble disese chrcterized by persistent respirtory symptoms tht typiclly include brethlessness (dyspne), chronic cough nd/or sputum production, nd irflow limittion due to irwy nd lveolr bnormlities ttributed to toxic environmentl gses nd prticles. 2 Ptients with COPD re lso subject to periods of symptom worsening, or excerbtions, which negtively impct helth sttus, increse hospitliztion rtes nd redmissions, nd contribute to disese progression. 2 Chronic irflow limittions my be cused by mixture of smll irwy disese nd prenchyml destruction, which vry from ptient to ptient nd my evolve t different rtes nd t different times. 2 Co-leding the webinr discussion ws Snjy Sethi, MD, professor of medicine, chief in the Division of Pulmonry, Criticl Cre nd Sleep Medicine, ssistnt vice president for Helth Sciences, nd medicl director of the University of Bufflo Clinicl Reserch Office. He ddressed key chllenges in dignosing nd treting ptients with COPD, given its wide vribility in presenttion: There is substntil proportion of ptients who hve COPD in their so-clled working yers, nd therefore tht cn hve substntil impct on their productivity. A publiction from The Americn Journl of Mnged Cre PROJ A838

2 C L I N I C A L B R I E F Tble 1. Severity of Airflow Limittion Assessment in Ptients With COPD 2, Clssifiction FEV 1 b GOLD 1 80% GOLD 2 50% - 79% GOLD 3 30% - 49% GOLD 4 <30% In ptients with spirometriclly confirmed dignosis of COPD (postbronchodiltor FEV 1 /FVC <0.70). b FEV 1 % predicted. COPD indictes chronic obstructive pulmonry disese; FEV 1, forced expirtory volume in 1 second; FVC, forced vitl cpcity; GOLD, Globl Inititive for Chronic Obstructive Lung Disese. Tble 2. GOLD ABCD Symptom nd Risk Assessment For Ptients With COPD 2 Group Excerbtion history 0 or 1 excerbtion(s) (not leding to hospitliztion) 2 excerbtions or 1 excerbtion(s) leding to hospitliztion Economic Impct of COPD COPD is responsible for substntil economic burdens on helthcre systems in the United Sttes. 4 COPD excerbtions nd ssocited hospitliztions ccount for the gretest proportion of the cost burden, with cler reltionship between disese severity nd cost of cre. 4 Totl ntionl medicl costs ttributble to COPD were estimted t $32.1 billion in 2010 nd re projected to rech $49 billion in In 2010, nerly 700,000 ptients were hospitlized for COPD, while 10.3 million were treted s outptients nd 1.5 million visited n emergency deprtment (ED). 5 The sme dt set from 2010 demonstrted tht indirect COPD-ttributble costs due to bsenteeism were estimted t $3.9 billion (in 2012 dollrs). 5 Chronic conditions ssocited with COPD my interfere with disese mngement nd contribute to hospitliztions. 2 Fctors driving the rising economic burden of COPD cn be ttributed to the ging US popultion coupled with the overll increse in helthcre utiliztion from COPD complicted by comorbidities nd the growth of totl medicl costs. 5 A C mmrc 0-1 CAT <10 B D mmrc 2 CAT 10 Symptom ssessment Evluted in ptients with spirometriclly confirmed COPD dignosis nd ssessment of irflow limittion by FEV 1 (GOLD 1-4). CAT indictes COPD Assessment Test; COPD; chronic obstructive pulmonry disese; FEV 1, forced expirtory volume in 1 second; GOLD, Globl Inititive for Chronic Obstructive Lung Disese; mmrc, modified Medicl Reserch Council dyspne scle. Andrew Cournoyer, RPh, MBA, vice president of formulry ccess solutions, Precision for Vlue, nd former senior director of Formulry nd Utiliztion Mngement, co-led of the presenttion, reemphsized the distribution of COPD ptients by ge nd Medicre eligibility. Cournoyer noted tht both ge groups (ie, those younger thn 65 yers nd the Medicre popultion) should hve equl weight cross ll lines of business [Medicre nd commercil]. Although rising costs ttributble to n ging popultion keep Medicre s priority in COPD discussions, the totl costs for both medicl nd phrmcy benefits need to be considered cross ge groups. Utiliztion mngement my offer opportunities to mitigte cost infltions due to rising medicl nd phrmcy costs. TREATMENT GOALS FOR COPD The GOLD report provides expert opinions nd recommendtions for clinicins on mintennce tretment for the short- nd long-term impcts of COPD, with the gols of relieving nd reducing symptom burdens nd risk of future excerbtions, improving qulity of life, nd reducing the risk of dverse events (AEs) nd disese progression. 2 GOLD recommendtions emphsize individulized tretment for ptients bsed on severity of symptoms, irflow limittion, nd severity of excerbtions. 2 Initil ssessment nd dignosis requires spirometry to confirm the presence of persistent irflow limittion in ptients with COPD symptoms, including dyspne nd chronic cough with or without sputum production. 2 Once dignosis is confirmed, the severity of irflow limittion is ssessed nd clssified s GOLD stge 1 to 4 (Tble 1). 2 The GOLD recommendtions include COPD ssessment tool which ctegorizes ptients bsed on respirtory symptoms (severity of brethlessness, nture nd mgnitude of symptoms) nd history of excerbtions to ssign ctegories (ABCD) of disese (Tble 2). 2 Phrmcologic tretment recommendtions re strtified by GOLD ABCD scle clssifictions for ech group of ptients (Figure 1) GOLD Tretment Recommendtions Phrmcologic therpy is the cornerstone of COPD mngement nd it is used to reduce symptoms, reduce frequency nd severity of excerbtions, nd improve exercise tolernce nd helth sttus. 2 Mny fctors influence the choice of therpeutic gent, including cost, vilbility, nd clinicl response, blnced with the AE profile of the mediction. 2 Combintion Therpy With Long-Acting Bronchodiltors Combintion therpy with long-cting bronchodiltors is centrl to the mngement of ptients with COPD. 2 For ptients with GOLD groups B, C, nd D disese, LAMA/LABA combintion therpies re the preferred tretment in the mjority of ptients with symptomtic COPD. 2 LAMAs bind to muscrinic receptors nd block the bronchoconstrictive effects of cetylcholine binding. The cholinergic receptors re locted on smooth muscle cells where ctivtion by cetylcholine increses peripherl irwy resistnce. 6 LABAs bind to the bet 2 receptor to induce bronchodiltion. Bet 2 -drenergic receptors 2

3 Clinicl Evidence Supporting the Evolving COPD Tretment Prdigm lso re locted on smooth muscle cells where ctivtion by bet 2 gonists results in relxtion of bronchil smooth muscle. 6 By combining therpies, different mechnisms of ction trget multiple receptor sites, which my hve dditive benefits for lung function nd the reduction of both symptoms nd the risk of excerbtions. 2 Combintion LAMA/LABA bronchodiltors my increse the degree of bronchodiltion with lower risk of AEs compred with incresing the dose of monotherpy. 2 Figure 1. Summry of Tretment Recommendtions by GOLD Grde 2,,b Group C LAMA + LABA Further excerbtion(s) LABA + ICS Group D Consider roflumilst if FEV 1 < 50% pred. nd ptient hs chronic bronchitis Further excerbtion(s) LAMA + LABA + ICS Consider mcrolide (in former smokers) Evolution of Chnges in GOLD Recommendtions for ICS Use GOLD recommendtions for the phrmcologic mngement of COPD no longer include ICS-contining regimens s the first-choice mintennce therpy in ny GOLD group. 2 Current GOLD-recommended strtegies include the use of LAMA, LABA, nd combintion LAMA/LABA s preferred tretments for symptomtic ptients with COPD, regrdless of excerbtion risk. 2 The GOLD report recommends LAMA/LABA bronchodiltor combintion therpy s preferred tretment over LABA/ICS therpy due to n incresed risk for developing pneumoni with ICS products. 2 Furthermore, this recommendtion ws implemented in the 2017 GOLD report nd reinforced in the 2018 GOLD report bsed prtilly on evidence demonstrting tht LAMA/LABA combintions re more effective t reducing the number of excerbtions compred with LABA/ICS combintions. 2 Group A LAMA/LABA/ICS triple therpy is recommended only for those ptients who develop irflow limittion, further evlution is wrrnted. further excerbtions while on LAMA/LABA combintion therpy. 2 Dr Sethi emphsized the importnce of dherence with recommendtions: ICS-contining regimens hve role, SAMA, short-cting muscrinic ntgonist. not s first-line therpy, but s dd-ons, nd triple therpy is lso only recommended if you hve further excerbtions beyond the use of the LAMA/LABA. CLINICAL EVIDENCE SUPPORTING A SHIFT IN THE PHARMACOLOGIC MANAGEMENT OF COPD LAMA Adverse Events With ICS Versus LAMA/LABA Therpies AEs re to be expected with ny phrmcologic tretment for COPD. However, the reltive impct nd/or seriousness of the AEs should be considered nd weighed in the blnce of tretment response. LAMA/LABA combintions re often ssocited with irwy AEs, such Continue, stop or try lterntive clss of bronchodiltor Evlute effect A bronchodiltor Further excerbtion(s) LAMA Group B LAMA + LABA LAMA + LABA Persistent symptoms Persistent symptoms/ further excerbtion(s) LABA + ICS A long-cting bronchodiltor (LABA or LAMA) Reprinted with permission from The Globl Inititive for Chronic Obstructive Lung Disese (GOLD) Globl strtegy for the dignosis, mngement, nd prevention of chronic obstructive pulmonry disese. Avilble t: Globl Inititive for Chronic Obstructive Lung Disese, All Rights Reserved. Green rrows nd box outlines represent preferred tretment. In ptients with mjor discrepncy between the perceived level of symptoms nd severity of b In Group A, bronchodiltor cn be short-cting (SABA or SAMA) or long-cting (LAMA or LABA), bsed on its effect on brethlessness. COPD indictes chronic obstructive pulmonry disese; FEV 1, forced expirtory volume in 1 second; GOLD, Globl Inititive for Chronic Obstructive Lung Disese; ICS, inhled corticosteroid; LABA, long-cting bet 2 gonist; LAMA, long-cting muscrinic receptor ntgonist; SABA, short-cting bet 2 ntgonist; s phryngitis nd nsophryngitis. 7-9 For ICS-contining products, Dr Sethi noted rnge in impct from nuisnce AEs, such s orophryngel cndidisis nd skin bruising, to incresed risk of ctrcts, dibetes, nd frctures. 10 The most concerning AE discussed in terms of clinicl nd economic impct ws pneumoni. Studies hve demonstrted tht ICS use is ssocited with n incresed risk of pneumoni in ptients with COPD. A 2016 met-nlysis of dt from 29 rndomized controlled trils (RCTs) nd 9 observtionl studies ssessed the risk of pneumoni in ptients tking ICS-contining therpy. The nlysis showed significntly incresed risk of pneumoni mong ICS users in the RCTs 3

4 C L I N I C A L B R I E F (reltive risk [RR], 1.61; 95% CI, ; P <.001) nd in the observtionl studies (odds rtio [OR], 1.89; 95% CI, ; P <.001). 11 In cse-control nlysis of 175,906 ptients with COPD, culled from helth dtbses in Quebec, Cnd, from Jnury 1, 1988, to December 31, 2001, dose-relted increse in the risk of hospitliztion for pneumoni nd of hospitliztion for pneumoni leding to deth ws shown mong ptients with COPD who were using ICS-contining products. 12 There ws dose-response reltionship, with the rte of pneumoni gretest with the highest doses of ICSs (RR, 2.25; 95% CI, ). 12 Conversely, the discontinution of ICS-contining products ws lso discussed. Using Quebec helth insurnce dtbses, investigtors formed cohort of 103,386 new users of ICSs nd followed them for pproximtely 5 yers. A totl of 14,020 serious pneumoni events occurred during this time. Discontinution of ICSs resulted in 37% decrese in the rte of serious pneumoni (rte rtio, 0.63; 95% CI, ). Moreover, the investigtors concluded tht ICSs were overused in COPD, counter to tretment recommendtions. 13 Mnging severe COPD brings incresing chllenges nd wreness of the impct of ICS use. Even though the GOLD report recommends ICS-contining regimens for more severe cses of COPD when LAMA/ LABA therpy does not control symptoms or excerbtions continue, group D ptients re t higher risk of developing pneumoni when treted with ICS-contining products. 2 The GOLD report lso notes tht more evidence supports the use of LAMA/LABA combintions over LABA/ ICS combintions in preventing excerbtions in group D ptients. 2 In ddition to the clinicl impct of these dt, Cournoyer discussed the substntil economic burden of pneumoni, prticulrly when hospitliztion is needed. Dt on community-cquired pneumoni were quntified in both inptient nd outptient settings in retrospective study of clims from lrge US helth pln from July 1, 2006, to December 31, Of the 28,575 pneumoni episodes exmined, 28% were treted in n inptient setting nd 72% were treted in n outptient setting. 14 Overll cost per episode reched $2212 for outptient mngement nd $27,661 for hospitlized ptients, with n verge cost per episode of more thn $ Cournoyer remrked, When we look t the overll popultion utilizing ICS regimens, this number [>$9000] might not be so insignificnt. It prompts the pyer to look t their dt nd not just look t the ICS utiliztion but lso the medicl impct tht might be hppening. Excerbtion Risk nd Control: ICS Versus LAMA/ LABA Combintion Therpies Dr Sethi noted tht clinicins historiclly relied on ICS products for reducing excerbtions, until dt emerged, somewht surprisingly, showing tht LAMA/LABA combintions were superior to ICS products for excerbtion control Multiple studies hve shown reduced frequency of excerbtions nd delys in time to first excerbtion with LAMA/LABA combintions compred with ICS-contining regimens (Tble 3) The results of the Informing the Pthwy of COPD Tretment (IMPACT) tril were relesed fter the webinr, which investigted the sfety nd efficcy of single-inhler triple therpy compred with LAMA/LABA nd LABA/ICS tretment once dily over 52 weeks to reduce the nnul rte of moderte or severe excerbtions in ptients with moderte-to-very-severe symptomtic COPD (N = 10,355). 18 Ptients in the triple therpy group experienced significntly lower rte of moderte or severe excerbtions compred with combintion LABA/ICS therpy (RR, 0.85; 95% CI, ; P <.001) nd combintion LAMA/LABA therpy (RR, 0.75; 95% CI, ; P <.001). 18 Additionlly, there ws higher incidence of pneumoni in the groups treted with ICS-contining regimens; the risk of pneumoni ws significntly higher with triple therpy compred with LAMA/LABA combintion (hzrd rtio [HR], 1.53; 95% CI, ; P <.001). 18 In response to the published results of the IMPACT tril, n editoril by Suiss nd Drzen in the New Englnd Journl of Medicine identified severl key issues in the tril design nd interprettion of results. 19 This editoril response dded merit to questioning the benefits of stepping up to triple therpy over dul bronchodiltion. Of the 10,355 ptients enrolled in the IMPACT tril, the mjority of the popultion ws receiving tretment with ICS-contining regimens; 38% of ptients were receiving tretment with triple therpy nd 29% were receiving tretment with LABA/ICS. 18 Upon rndomiztion to the LAMA/LABA tretment rm, ptients previously treted with n ICS-contining regimen were bruptly withdrwn from tretment nd indvertently stepped down in therpy. 19 This discontinution of the ICS component of tretment my hve contributed to the incresed excerbtion rte within 1 month of rndomiztion reported in the LAMA/LABA tretment rm compred with the triple therpy nd LABA/ICS tretment rms. 19 Additionlly, Suiss nd Drzen noted tht during the subsequent 11 months of follow-up, the incidence of excerbtion in the LAMA/LABA tretment rm ws nerly the sme s reported in the triple therpy rm. 19 Suiss nd Drzen concluded tht the results of the IMPACT tril do not support stepping up to triple therpy in clinicl prctice nd recommended tht until high-qulity evidence supports the ddition of ICS to LAMA/LABA therpy, escltion to triple therpy should be reserved for symptomtic ptients in GOLD group D, s supported by the GOLD 2017 nd 2018 reports. 2,19 Figure 2 shows the lrger body of evidence supporting LAMA/ LABA combintions versus LABA/ICS combintions with comprison of impct on lung function. 16,17,20-24 ICS Withdrwl Multiple studies hve shown tht withdrwing ICS from tretment showed no chnge in risk of excerbtions. Three trils WISDOM, OPTIMO, nd INSTEAD demonstrted tht ptients mintined on bronchodiltor therpy did not experience n incresed risk of excerbtions fter withdrwl of ICSs In the lrgest of the 3 trils, the 52-week WISDOM tril enrolled 2485 ptients with history of excerbtions to receive triple combintion therpy twice dily or be treted with triple therpy initilly with systemtic dosge reduction of the ICS every 6 weeks. There were no sttisticlly significnt differences in the risk of moderte to severe excerbtions (HR, 1.06; 95% CI, ) or frequency of excerbtions (HR, 1.20; 95% CI, ) between ptients who 4

5 Clinicl Evidence Supporting the Evolving COPD Tretment Prdigm Tble 3. LAMA/LABA Clinicl Efficcy Reducing Excerbtion Risk in Ptients With COPD Efficcy Outcomes Tril Popultion Tretment Rte of Excerbtion RR (95% CI) P vlue Time to First Excerbtion HR (95% CI) P vlue FLAME Enrolled ptients with COPD nd history of t lest 1 excerbtion during the previous yer (N = 3362) Rndomized (1:1) to receive either tretment for 52 weeks: LAMA/LABA (n = 1680) 50/110 μg once dily LABA/ICS (n = 1682) 50/500 μg twice dily 11% reduction in nnul rte of ll COPD excerbtions with LAMA/LABA vs LABA/ICS 17% reduction in nnul rte of moderte or severe COPD excerbtions with LAMA/LABA vs LABA/ICS RR, 0.89 (95% CI, ) P =.003 RR, 0.83 (95% CI, ) P < % longer time to first excerbtion with LAMA/LABA vs LABA/ICS 16% reduced risk of excerbtion with LAMA/LABA vs LABA/ICS 51 dys vs 71 dys HR, 0.84 (95% CI, ) P <.001 ILLUMINATE Enrolled ptients with moderteto-severe COPD without history of excerbtions in the previous yer (N = 523) Rndomized (1:1) to receive either tretment for 26 weeks: LAMA/LABA (n = 258) 50/110 μg once dily LABA/ICS (n = 264) 50/500 μg twice dily Comprble results in terms of frequency of COPD worsening, including excerbtion, in ptients treted with LAMA/LABA vs LABA/ICS (17.1% vs 23.5%) LANTERN Enrolled ptients with moderte-tosevere COPD with history of no more thn 1 excerbtion in the previous yer (N = 744); 50% of ptients clssified s GOLD group D Rndomized (1:1) to receive either tretment for 26 weeks: LAMA/LABA (n = 372): 50/110 μg once dily LABA/ICS (n = 372): 50/500 μg twice dily 31% reduction in nnul rte of moderte or severe excerbtions with LAMA/LABA vs LABA/ICS RR, 0.69 (95% CI, ) P = % reduced risk of moderte or severe excerbtion with LAMA/LABA vs LABA/ICS tretment HR, 0.65 (95% CI, ) P =.028 COPD indictes chronic obstructive pulmonry disese; GOLD, Globl Inititive for Chronic Obstructive Lung Disese; HR, hzrd rtio; ICS, inhled corticosteroid; LABA, long-cting bet 2 gonist; LAMA, long-cting muscrinic receptor ntgonist; RR, rte rtio. Across ll studies, LAMA/LABA tretment ws glycopyrronium (LAMA) nd indcterol (LABA); LABA/ICS tretment ws slmeterol (LABA) nd fluticsone (ICS). continued with the ICS compred with those withdrwn from ICS. 25 Additionlly, ptients withdrwn from ICS experienced sttisticlly significnt decrese in lung function compred with ptients who continued triple therpy (P =.001) by the 52-week mrk of the study. 25 In the OPTIMO study, ptients t low risk of excerbtion receiving ICS plus bronchodiltor mintennce experienced no deteriortion of lung function symptoms, nd excerbtion rte ws similr 6 months fter ICS withdrwl when pproprite mintennce therpy with bronchodiltors ws mintined compred with ptients who continued ICS tretment (26% vs 29%, respectively). 26 Results from the INSTEAD study demonstrted tht ptients t low risk of excerbtions who were switched from LABA/ICS combintion to LABA monotherpy (n = 293) hd no evidence of n incresed rte of excerbtions compred with ptients who continued to receive the LABA/ICS tretment (n = 288) over the 26-week study period (excerbtion rte of 0.57 nd 0.67 per yer, respectively). 27 As noted previously, dt hve shown tht discontinution of ICS lso resulted in reduced risk of pneumoni. 13 The clinicl benefit of bronchodiltion for improved lung function, s well s withdrwl of ICSs with no increse in excerbtion risk, re considertions for pyers during their review of the full body of clinicl evidence surrounding phrmcologic therpy for COPD to mke informed decisions. Cournoyer noted, These re the outcomes tht we s pyers like to see when considering totl medicl cost reduction. This evidence supports clinicl policy, [nd] considering mngement inititives, it gives us bsis or footing to stnd on tht we re bsing [our decision] upon scientific, peerreviewed, evidence-bsed guideline to support the premise of tht prticulr policy. Ultimtely, if pyers re going to look t utiliztion mngement progrms, it s this type of evidence tht they relly look for to help crete tht policy nd defend tht policy. Consequences of Rel-World Nondherence to GOLD Recommendtions Despite GOLD recommendtions for LAMA/LABA combintion therpy s the preferred tretment in the mjority of ptients, the most common medictions used to tret COPD re LABA/ICS combintions, followed by LAMA monotherpy nd triple therpy. 28 The most common combintions used to tret ptients with COPD were demonstrted in relworld nlysis of clims from ptients with COPD (N = 358,199). 28 5

6 C L I N I C A L B R I E F Figure 2. The Clinicl Evidence Supporting Improvements in Lung Function With LAMA/LABA Versus LABA/ICS 16,17,20-24, 120 Lung Function Men Difference in Drough FEV 1 for LAMA/LABA vs LABA/ICS (ml) Study 16 95% CI, 25-58; P < ±14 P = % CI, ; P <.0001 Rbe et l Mgnussen et l Vogelmeier et l 2008 b 2012 c 2013 (ILLUMINATE) d 75 95% CI, ; P <.001 Zhong et l 2015 (LANTERN) d 82 95% CI, ; P <.001 Donohue, et l 2015 (DB ) e 98 95% CI, ; P <.001 Donohue et l 2015 (DB ) e 90 95% CI, ; P < % CI, 34-82; P <.0001 Singh et l Beeh et l 2015 e 2016 f (ENERGITO) Follow-up Severity, FEV 1 6 weeks 8 weeks (2 times) 26 weeks 26 weeks 12 weeks 12 weeks 12 weeks 6 weeks (4 times) 65% 65% 40% to 80% 30% to <80% 30% to 70% 30% to 70% 30% to 70% 30% to <80% LAMA/LABA (n) LABA/ICS (n) n = 304 n = 172 switch to LABA/ICS n = 157 n = 301 n = 172 switch to LAMA/LABA n = 160 n = 258 n = 372 n = 353 n = 349 n = 358 n = 221 n = 264 n = 369 n = 353 n = 348 n = 358 n = 219 COPD indictes chronic obstructive pulmonry disese; FEV 1, forced expirtory volume in 1 second; ICS, inhled corticosteroid; LABA, long-cting bet 2 gonist; LAMA, long-cting muscrinic receptor ntgonist; ±, stndrd devition. LABA/ICS tretment with slmeterol/fluticsone (50/500 µg or 50/250 µg). b LAMA/LABA tretment with tiotropium (18 µg) plus formoterol (12 µg). c LAMA/LABA tretment with tiotropium (18 µg) plus slmeterol (50 µg). d LAMA/LABA tretment with glycopyrronium/indcterol (50/110 µg). e LAMA/LABA tretment with umeclidinium/vilnterol (62.5/25 µg). f LAMA/LABA tretment with tiotropium/olodterol (5/5 µg). Dt not shown for tretment rms of lterntive doses. Overtretment with ICS-contining regimens ws observed, s the mjority of ptients with COPD were treted with n ICS-contining regimen (72%); 26.1% were prescribed triple therpy, nd 45.6% were treted with n LABA/ICS combintion (Figure 3). 28 Of the ptients receiving triple therpy, more thn hlf of the popultion (52.6%) did not hve history of excerbtions (Figure 4). 28 Triple therpy is recommended for ptients with severe symptoms nd high risk of excerbtions fter persistent COPD symptoms nd excerbtions with LAMA/LABA tretment. Despite this recommendtion, only 8.6% of the popultion treted with triple therpy hd history of severe excerbtions. 2,28 Cournoyer highlighted the impct of nondherence to GOLD recommendtions nd pyer concerns with elevted helthcre resource utiliztion. He stted tht the 72% of ptients receiving n ICS-contining regimen nd the 26% of ptients receiving the most ggressive form of therpy, triple therpy, re the res I would look t. The sfety component is nother re tht pyers my scrutinize when considering utiliztion mngement. Cournoyer dded, We highlighted pneumoni nd wht tht cost of the dded risk might look like. It s these types of fctors tht mke me wnt to think bout my utiliztion nd my prticulr pln. He dded tht these dt present n opportunity to improve not only ptient outcomes, but lso the downstrem impct on medicl cost offsets nd possibly even drug svings. There is mesurble impct of nondherence to GOLDrecommended tretment strtegies on ptient outcomes nd ssocited helthcre utiliztion. In study of electronic helth records from Jnury 1, 2007, to December 31, 2012 (N = 4234 treted ptients), investigtors ssessed the effect of dherence nd nondherence to GOLD 2011 prescribing recommendtions on COPD symptom burden, excerbtions, nd helthcre resource utiliztion during the 180 dys following index tretment strt. 29 GOLD-dherent prescribing prctices were ssocited with significnt reductions in ll-cuse hospitliztions nd ED visits compred with nondherent prctices (OR, 0.69 nd 0.63, respectively) (Figure 5). 29 GOLD-dherent prescribing ws ccompnied by significnt decrese in ll-cuse ED visits compred with overtretment (OR, 0.61; P =.0042). 29 Cournoyer noted tht in these dt, we cn potentilly see medicl cost offsets 6

7 Clinicl Evidence Supporting the Evolving COPD Tretment Prdigm 1 column Figure 3. Rel-World Prescribing Prctices Nondherent With GOLD-Recommended Long- Acting Mintennce Tretment 28 Long-Acting Mintennce Tretment 1 column Figure 4. Rel-World Triple Therpy Prescribing Prctices Nondherent with GOLD- Recommended COPD Tretment Strtegies 28 Excerbtion History in Ptients Treted With Triple Therpy LABA only 1.0% LAMA/LABA 0.8% Severe excerbtions 8.6% LAMA only 26.5% Triple therpy 26.1% Moderte excerbtions 17.7% No excerbtions 52.6% 72% of ptients were prescribed n ICS-contining recommendtion LABA/ICS only 45.6% Mild excerbtions 21.1% GOLD indictes Globl Inititive for Chronic Obstructive Lung Disese; ICS, inhled corticosteroid; LABA, long-cting bet 2 gonist; LAMA, long-cting muscrinic receptor ntgonist. Bsed on clims dt from Jnury 1, 2010, to June 30, 2015, for ptients with COPD (N = 358,199). COPD indictes chronic obstructive pulmonry disese; GOLD, Globl Inititive for Chronic Obstructive Lung Disese. Bsed on clims dt from Jnury 1, 2010, to June 30, 2015, for ptients with COPD receiving triple therpy (N = 31,660). b Excerbtions were physicin defined nd occurred 12 months prior to index dte. when we re GOLD-dherent nd steering ptients to be dherent with [the] GOLD. Tht [informs] the medicl piece. Drug costs for COPD hve not historiclly held much concern for pyers, lrgely overshdowed by medicl costs from hospitliztions nd ED visits s result of excerbtions. However, triple therpy entered the mrket t higher price point. 30 The phrmcy spend on triple therpy ($530) is 50% more expensive thn LAMA monotherpy ($324-$398) or LAMA/LABA combintion therpy ($355- $398) for 30-dy supply. 30 Coupled with the risks of AEs with ICS use, specificlly pneumoni, the utility of triple therpy will likely initite further discussion mong pyers to consider utiliztion mngement strtegies. 11 APPROPRIATE ICS USE: CONSIDERATIONS FOR MANAGED CARE Tretment with ICS-contining therpies for ptients with COPD is the most ggressive form of mintennce mediction nd is ssocited with incresed helthcre resource utiliztion. Pyers will consider nondherence to recommendtions, incresed phrmceuticl costs, nd dded helthcre costs due to AEs s result of ggressive therpy. Cournoyer discussed tht the rel-world dt showing 72% rte of utiliztion of ICS-contining tretment regimens dd to concerns bout nondherence to the GOLD recommendtions: The ICS component is not primry tretment option in most groups, nd is second-line in group D, which doesn t promote ICSs s frontline tretment. Pyers re concerned with this high rte of utiliztion, coupled with AEs from ICS usge. According to Cournoyer, Pneumoni comes with cost. Pyers re concerned with helthcre resource utiliztion nd minimizing [the] cost of AEs tied to pneumoni, s well s ssocited outptient nd inptient costs. He emphsized the importnce of pyers reviewing the dt on utiliztion of these ICS-contining regimens in their popultions nd seeing if this popultion ws ssocited with hospitliztions for pneumoni. These nlyses would support decision mking nd step edits round the usge of ICSs to minimize inpproprite use. Cournoyer discussed how these intersecting fctors could spur interest in pyer mngement of triple therpy. There s the guidelines [component]. Secondly, there re the inpproprite utiliztion trends tht ultimtely re components of the totl medicl cost spend. There s the cost sving opportunity from both the medicl nd phrmcy points of view. Bsed on these issues, pyers should probbly tke step bck, look t their dt, nd initite dilogue to determine if these pertin to their pln, he sid. If so, Cournoyer posed questions for pyers to consider: Do the guidelines give us clinicl justifiction to mnge this? Does this drive improved ptient outcomes such s cre mngement progrms nd cse mngement interventions? ICS-contining regimens re not beneficil for ll ptients with COPD nd the GOLD recommends limiting the use of ICSs to tht of dd-on therpy. 2 Considering the GOLD ABCD tretment model, pyers my find opportunity by including step therpy tht is guided by the GOLD lgorithm. 2 Cournoyer summrized potentil decision process for COPD mngement: The type of utiliztion mngement strtegy would be step therpy becuse of its point-of-sle opertions. Overll, the clss.contins highly utilized drugs, nd I think putting something 7

8 C L I N I C A L B R I E F Figure 5. Effect of GOLD-Adherent nd -Nondherent Prescribing Prctices During 180 Dys Following Strt of Index Tretment 29 COPD-relted symptoms HCRU Odds Rtio (95% CI) GOLD-Adherent vs -Nondherent like prior uthoriztion out there tht s hrd stop t the point of sle would put lot of burden on the precertifiction deprtments. He noted tht prior uthoriztion would be especilly burdensome in the precertifiction deprtment in Medicre setting. As providers nd pyers continue to look for solutions in the new COPD tretment prdigm, Cournoyer noted tht pyers do hve some bsis to crete such policy nd gin support through phrmcy nd therpeutics committees becuse we hve the pproprite scientific evidence. So the question is, is your COPD popultion GOLD-dherent? P vlue Shortness of breth 0.83 ( ).0046 Cough 0.77 ( ).0000 Wheezing 0.76 ( ).0001 Fewer ctivities 0.79 ( ).0037 Other symptoms 0.75 ( ).0000 All-cuse Hospitliztion 0.69 ( ).0169 ED visit 0.63 ( ).0035 Respirtory-specific Hospitliztion 0.81 ( ).4686 ED visit 0.65 ( ) Fvors GOLD dherent Fvors GOLD nondherent Reprinted with permission from Chronic Obstructive Pulmonry Diseses: Journl of the COPD Foundtion. 29 Defined using the GOLD 2011 recommendtions for phrmcologic therpy. COPD indictes chronic obstructive pulmonry disese; ED, emergency deprtment; GOLD, Globl Inititive for Chronic Obstructive Lung Disese; HCRU, helthcre resource utiliztion. cse mngement interventions. 2 CONCLUSIONS COPD mngement for evidence-bsed decision mking. Despite mounting evidence, rel world dt show frequent use nd overtretment with ICS-contining regimens, including the higher-cost triple therpy. 28 LAMA/LABA therpy improves lung function nd reduces excerbtion risk compred with LABA/ICS combintions. 20 Additionlly, ptients mintined on bronchodiltor therpy did not experience n incresed risk of excerbtions fter withdrwl of ICSs ICS-contining therpies hve role in the mngement of COPD, but they re not recommended s the preferred initil tretment in the mjority of ptients with COPD. 2 ICS use is ssocited with n incresed risk of pneumoni, n often serious nd costly AE. 11 GOLD recommendtions note tht ICS-contining therpies should be used when the preferred mediction does not offer symptom control. 2 Formulry decision mkers my wnt to consider the growing body of evidence tht supports more limited role for ICS-contining regimens thn wht is currently in use. Understnding the role of ICS-contining therpy nd its plce within the tretment lgorithm for ptients with COPD in groups B, C, nd D could help decision mkers implement pproprite strtegies to improve ptient outcomes, which my include cre mngement progrms or To conclude the AMCP Science nd Innovtion Theter Webinr, Cournoyer reiterted, Pyers understnd the guidelines nd look t their dt. If they hven t reviewed the new GOLD [recommendtions], then mybe it s time to tke look nd understnd the pproprite roles nd plces of therpy for the vrious drugs nd when to use them for mintennce. Addressing the Chllenges nd Unmet Needs in GOLD Adherence for COPD There is n opportunity for mnged cre to improve outcomes by nlyzing current utiliztion trends nd compring them with GOLD recommendtions. Given tht nondherence to GOLD recommendtions is ssocited with high resource utiliztion, decision mkers cn reevlute the ppropriteness of strtegies in their popultion of ptients with COPD. 29 Decision mkers re uniquely positioned to nlyze the dt which highlight the chllenges nd unmet needs in the current stte of REFERENCES 1. Globl Inititive for Chronic Obstructive Lung Disese (GOLD) Globl strtegy for the dignosis, mngement, nd prevention of chronic obstructive pulmonry disese. GOLD website. org. Published Jnury Accessed My 29, Globl Inititive for Chronic Obstructive Lung Disese (GOLD) Globl strtegy for the dignosis, mngement, nd prevention of chronic obstructive pulmonry disese. GOLD website. org. Published Jnury Accessed My 29, Wheton AG, Cunninghm TJ, Ford ES, Croft JB; Centers for Disese Control nd Prevention. Employment nd ctivity limittions mong dults with chronic obstructive pulmonry disese United Sttes, MMWR Morb Mortl Wkly Rep. 2015:64(11): Dll AA, Liu F, Riedel AA. Cost trends mong commercilly insured nd Medicre Advntge-insured ptients with chronic obstructive pulmonry disese: 2006 through Int J Chron Obstruct Pulmon Dis. 2011;6: doi: /COPD.S

9 Clinicl Evidence Supporting the Evolving COPD Tretment Prdigm 5. Ford ES, Murphy LB, Khvjou O, Giles WH, Holt JB, Croft JB. Totl nd stte-specific medicl nd bsenteeism costs of COPD mong dults ged 18 yers in the United Sttes for 2010 nd projections through Chest. 2015;147(1): doi: /chest Brnes PJ, Burney PG, Silvermn EK, et l. Chronic obstructive pulmonry disese. Nt Rev Dis Primers. 2015;1: doi: /nrdp Stiolto Respimt [prescribing informtion]. Ridgefield, CT: Boehringer Ingelheim Phrmceuticls, Inc; docs.boehringer-ingelheim.com/prescribing%20informtion/pis/stiolto%20respimt/stiolto.pdf. 8. Anoro Ellipt [prescribing informtion]. Reserch Tringle Prk, NC: GlxoSmithKline; Utibron Neohler [prescribing informtion]. Est Hnover, NJ: Sunovion Phrmceuticls Inc; Price D, Ywn B, Brusselle G, Rossi A. Risk-to-benefit rtio of inhled corticosteroids in ptients with COPD. Prim Cre Respir J. 2013;22(1): doi: /pcrj Festic E, Bnsi V, Gupt E, Scnlon PD. Assocition of inhled corticosteroids with incident pneumoni nd mortlity in COPD ptients; systemtic review nd met-nlysis. COPD. 2016;13(3): doi: / Ernst P, Gonzlez AV, Brssrd P, Suiss S. Inhled corticosteroid use in chronic obstructive pulmonry disese nd the risk of hospitliztion for pneumoni. Am J Respir Crit Cre Med. 2007;176(2): doi: /rccm OC. 13. Suiss S, Coulombe J, Ernst P. Discontinution of inhled corticosteroids in COPD nd the risk reduction of pneumoni. Chest. 2015;148(5): doi: /chest Sto R, Gomez Rey G, Nelson S, Pinsky B. Community-cquired pneumoni episode costs by ge nd risk in commercilly insured US dults ged 50 yers. Appl Helth Econ Helth Policy. 2013;11(3): doi: /s Wedzich JA, Bnerji D, et l; the FLAME Investigtors. Indcterol-glycopyrronium versus slmeterolfluticsone for COPD. N Engl J Med. 2016;374(23): doi: /NEJMo Vogelmeier CF, Btemn ED, Pllnte J, et l. Efficcy nd sfety of once-dily QVA149 compred with twice-dily slmeterol-fluticsone in ptients with chronic obstructive pulmonry disese (ILLUMINATE): rndomised, double-blind, prllel group study. Lncet Respir Med. 2013;1(1): doi: /S (12) Zhong N, Wng C, Zhou X, et l; LANTERN Investigtors. LANTERN: rndomized study of QVA149 versus slmeterol/fluticsone combintion in ptients with COPD. Int J Chron Obstruct Pulmon Dis. 2015;10: doi: /COPD.S Lipson DA, Brnhrt F, Breley N, et l; IMPACT Investigtors. Once-dily single-inhler triple versus dul therpy in ptients with COPD. N Engl J Med. 2018;378(18): doi: /NEJMo Suiss S, Drzen JM. Mking sense of triple inhled therpy for COPD. N Engl J Med. 2018;378(18): doi: /NEJMe Rbe KF, Timmer W, Sgkriotis A, Viel K. Comprison of combintion of tiotropium plus formoterol to slmeterol plus fluticsone in moderte COPD. Chest. 2008;134(2): doi: /chest Mgnussen H, Pggiro P, Schmidt H, Kesten S, Metzdorf N, Mltis F. Effect of combintion tretment on lung volumes nd exercise endurnce time in COPD. Respir Med. 2012;106(10): doi: /j.rmed Donohue JF, Worsley S, Zhe CQ, Hrdker L, Church A. Improvements in lung function with umeclidinium/vilnterol versus fluticsone propionte/slmeterol in ptients with moderte-to-severe COPD nd infrequent excerbtions. Respir Med. 2015;109(7): doi: /j.rmed Singh D, Worsley S, Zhu CQ, Hrdker L, Church A. Umeclidinium/vilnterol versus fluticsone propionte/ slmeterol in COPD: rndomised tril. BMC Pulm Med. 2015;15:91. doi: /s Beeh KM, Derom E, Echve-Sustet J, et l. The lung function profile of once-dily tiotropium nd olodterol vi Respimt is superior to tht of twice-dily slmeterol nd fluticsone propionte vi Accuhler (ENERGITO study). Int J Chron Obstruct Pulmon Dis. 2016;11: doi: /COPD.S Mgnussen H, Disse B, Rodriguez-Roisub R, et l; the WISDOM Investigtors. Withdrwl of inhled glucocorticoids nd excerbtions of COPD. N Engl J Med. 2014;371(14): doi: /NEJMo Rossi A, Guerriero M, Corrdo A; OPTIMO/AIPO Study Group. Withdrwl of inhled corticosteroids cn be sfe in COPD ptients t low risk of excerbtion: rel-life study on the ppropriteness of tretment in moderte COPD ptients (OPTIMO). Respir Res. 2014;8;15:77. doi: / Rossi A, vn der Molen T, del Olmo R, et l. INSTEAD: rndomised switch tril of indcterol versus slmeterol/fluticsone in moderte COPD. Eur Respir J. 2014;44(6): doi: / Dt on file. Boehringer Ingelheim. 29. Mnnino DM, Yu TC, Zhou H, Higuchi K. Effects of GOLD-dherent prescribing on COPD symptoms burden, excerbtions, nd helth cre utiliztion in rel-world setting. Chronic Obstr Pulm Dis. 2015;2(3): doi: jcopdf Micromedex RED BOOK (electronic version). Truven Helth Anlytics, Greenwood Villge, CO. Accessed My 29,

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