PresenterDisclosure

•  Speaker:Dr.CharlesChan•  Rela1onshipswithcommercialinterests:

–  Grants/ResearchSupport:N/A–  SpeakersBureau/Honoraria:AZ,BI,Merck,Novar1s–  Consul1ngFees:AZ,Novar1s–  Other:CPSO,OHA,HQO

2

LearningObjec5ves

A8ertakingpartinthisprogram,par5cipantswillbebe?erableto:

•  Iden5fypa5entswithCOPDatriskforexacerba5ons

•  PreventCOPDexacerba5onsthroughtherapeu5cinterven5ons

•  ManageCOPDexacerba5onsappropriately

3COPD=chronicobstruc5vepulmonarydisease

Whatisanexacerba5on?

4

GOLD=GlobalIni5a5veforChronicObstruc5veLungDisease;WHO=WorldHealthOrganiza5onAnthonisenNRetal.AnnInternMed1987;106:196-204.GlobalIni5a5veforCOPD,Nov2011.Availableat:www.goldcopd.org.

Management-DrivenDefini1on:GOLDWHOCOPDDocument2011

Clinically-BasedDefini1on:AnthonisenCriteria

Arecharacterizedby:

•  Increasedsputumvolume•  Increasedsputum

purulence•  Worseningdyspnea

“Anacuteeventcharacterizedbyaworseningofapa5ent’s

respiratorysymptomsthatisbeyondnormal

day-to-dayvaria5onsandleadstoachangeinmedica5on.”

ImpactofExacerba5onsinCOPD

5

Highermortality

Increasedhealthcareu1liza1on

WedzichaJA,SeemungalTA.Lancet2007;370:786-796.

Pa1entswithfrequentexacerba1ons

Fasterdeclineinlungfunc1on

Poorerqualityoflife

DiseaseSeverityandPreviousExacerba5onsPredictFrequencyandSeverityofExacerba5ons

6Note:frequentexacerba5onsweredefinedastwoormoreexacerba5onsinthefirstyearofthestudy.HurstJRetal.NEnglJMed2010;363:1128-38.

7

18

33

22

33

47

0

10

20

30

40

50

GOLD2(n=945)

GOLD3(n=900)

GOLD4(n=293)

Hospitalizedforexacerba5oninyrone Frequentexacerba5ons

%ofp

a1en

ts

Year3

0 20 40 60 80 100Percent

0 20 40 60 80 100Percent

0 20 40 60 80 100Percent

0 20 40 60 80 100Percent

Year1 Year2

0 20 40 60 80 100

0 20 40 60 80 100

Percent

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

0 20 40 60 80 100

23%6%2%

6%3%2%

2%2%1%

5%3%1%

3%2%2%

2%2%3%

2%1%1%

2%2%3%

1%4%12%

71%whowerefrequentexacerbatorsinyears1&2

werealsofrequentexacerbatorsinyear3

74%whowereinfrequentexacerbatorsinyears1&2

werealsoinfrequentexacerbatorsinyear3

Themajorityofpa5entsarenotfrequentexacerbators

60%ofthesewerealsofrequentexacerbators

inyear2

83%ofthesewerealsoinfrequentexacerbators

inyear2

7HurstJRetal.NEnglJMed2010;363:1128-38.

Pa5entswithnoexacerba5onPa5entswith1exacerba5onPa5entswith≥2exacerba5ons

29%werefrequentexacerbatorsinyear1

71%wereinfrequentexacerbatorsinyear1

Pa5entsTendtobeEitherFrequentExacerbatorsorNot:PhenotypeisStable

Pa5entswithGERDAreMoreLikelytoBeFrequentExacerbators

8

23%$

13%$

0%$

5%$

10%$

15%$

20%$

25%$

GERD$ No$GERD$

*

*p <0.0001

Percen

twith

≥2exacerba

1onsperyear

Note:frequentexacerba5onsweredefinedastwoormoreexacerba5onsperyear.GERD=gastroesophagealrefluxdiseaseMar5nezCHetal.RespirRes2014;15:62.

Pa5entswithChronicCoughandSputumProduc5onAreMoreLikelytoBeFrequentExacerbators

9

55%#

22%#

0%#

10%#

20%#

30%#

40%#

50%#

60%#

Chronic#cough#and#sputum#produc9on# No#chronic#cough#and#sputum#

*

Percen

twith

≥2exacerba

1onsperyear

Note:frequentexacerba5onsweredefinedastwoormoreexacerba5onsperyear.BurgelP-Retal.Chest2009;135:975-82.

*p <0.0001

Whoisatriskforfrequentexacerba5ons?

ClinicalTips

Pa5entswhoareatriskarethosewith:

•  Moreseveredisease(FEV1<50%predicted)•  Historyof≥twoexacerba5ons/year•  GERD•  Symptomsofchronicbronchi5s(chroniccoughandsputumproduc5on)

10

BurgelP-Retal.Chest2009;135:975-82;HurstJRetal.NEnglJMed2010;363:1128-38;Mar5nezCHetal.RespirRes2014;15:62.

Evidence-BasedInhaledPharmacologicalTherapiestoPreventExacerba5ons

11

Class Individualagents(inalphabe5calorder)

LABAFormoterolIndacaterolSalmeterol

LAMAAclidinium

GlycopyrroniumTiotropium

Umeclidinium

LABA/LAMAFormoterol/aclidinium

Indacaterol/glycopyrroniumOlodaterol/5otropiumVilanterol/umeclidinium

LABA/ICSFormoterol/budesonideSalmeterol/flu5casoneVilanterol/flu5casone

ICS=inhaledcor5costeroid;LABA=long-ac5ngβ2-agonist;LAMA=long-ac5ngmuscarinicantagonist.Adaptedfrom:CrinerGJetal.Chest2015;147:894-942.

AdherencetoInhaledMedica5onReducesRiskofSeriousExacerba5ons

0.15

0.27

0

0.05

0.1

0.15

0.2

0.25

0.3

Goodadherence(n=4880) Pooradherence(n=1232)

Annu

alra

teofh

ospitaladm

ission

fore

xacerba1

on

p<0.001

Note:goodadherencewasdefinedas>80%useofstudymedica5on.VestboJetal.Thorax2009Nov;64:939-43. 12

IndacaterolMonotherapyIncreasesTimetoFirstExacerba5onvs.Placebo:PooledPostHocAnalysis

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

Placebo(n=1151)

Indacaterol150μg(n=746)

Indacaterol300μg(n=819)

Annu

alized

rateofC

OPD

exacerba

1ons -31%-29%

RR=0.69**(95%CI0.55–0.87)

RR=0.71**(95%CI0.57–0.88)

Dataareexacerba5ons/pa5ent/yearwithRRsfortreatmentdifferences

**p<0.002vs.placebo

100

90

80

70

60

0

Timetofirstexacerba1on(months)Pa

1entse

xacerba1

onfree(%

)

0123456

Indacaterol150μgIndacaterol300μgPlacebo

No.atriskIndacaterol150μg 746 678 625 592 560 534 453Indacaterol300μg 819 731 691 652 622 597 538Placebo 1151 969 881 803 749 713 634

Note:ThesedosesofindacaterolarenotavailableinCanada,exceptforthe150µgdose,theequivalentofwhichisavailableinfixed-dosecombina5onwithglycopyrronium.CI=confidenceinterval;RR=ratera5o.WedzichaJAetal.RespirMed2015;109:105-11.

13

GlycopyrroniumandTiotropiumMonotherapiesProlongTimetoFirstModerate-to-Severe

COPDExacerba5onvs.Placebo:GLOW2Study

0481216202428323640444852

100

90

80

70

60

50

40

Timetofirstexacerba1on(weeks)

Pa1e

ntse

xacerba1

onfree(%

) Glycopyrronium50μgodTiotropium18μgodPlacebo

KerwinEetal.EurRespirJ2012;40:1106-14. 14

RateReduc5onofCOPDExacerba5onswithIndacaterol/Glycopyrroniumvs.GlycopyrroniumandTiotropiumMonotherapies:SPARKStudy

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Mildexacerba5ons Moderate/severeexacerba5ons

Severeexacerba5ons Allexacerba5ons

COPD

exacerba1

ons(an

nualized

rate)

0.84*(0.75,0.95)

0.85†(0.75,0.96)

0.88§(0.77,0.99)

0.90‡(0.79,1.02)

1.16¶(0.84,1.61)

0.81||(0.60,1.10)

0.85††(0.77,0.94)

0.86**(0.78,0.94)

Valuesareratera5os(95%CI);nnumberspertreatmentgroup:Indacaterol/glycopyrroniumn=729;glycopyrroniumn=739;5otropiumn=737*p=0.0052,†p=0.0072,‡p=0.096,§p=0.038,¶p=0.36,||p=0.18,**p=0.0017,††p=0.0012WedzichaJAetal.LancetRespirMed2013;1:199-209.

Indacaterol/glycopyrroniumGlycopyrroniumTiotropium

15

BenefitsofDualbronchodilators:PharmacologicalRa5onaleforCombiningLABAsandLAMAs

Complementaryroutesleadingtobronchodila1onviaindirectanddirectrelaxa1onofsmoothmuscle

LAMAs LABAs

CazzolaM,MolimardM.PulmonaryPharmacology&Therapeu5cs23(2010)257e267

TripleTherapyDecreasedExacerba5onsvs.TiotropiumAlone:CLIMBStudy

0

0.1

0

Exacerba

1ons/pa1

ent

Dayssincerandomiza1on15 30 45 60 75 90

0.2

0.3

0.4

PBO+TIOBUD/FORM+TIO

PBO=placebo;TIO=5otropium;BUD=budesonide;FORM=formoterol.n=60;RR=0.38(95%CI,0.25–0.57;p<0.001)Note:rateofexacerba5onswasnottheprimaryendpointofthisstudy.Welteetal.AmJRespirCritCareMed2009;180:741-50. 17

ShouldwebeconcernedaboutICSuse?

CAP=community-acquiredpneumoniaNote:seriouspneumoniawasdefinedaspneumoniaresul5nginhospitaliza5onordeathSuissaSetal.Thorax2013;68:1029-36.

CurrentuseofICSisassociatedwitha69%increaseintherateofseriouspneumonia(RR1.69;95%CI1.63–1.75)

163,514ptswithCOPD20,344hadseriousCAP

0200400600800100012001400160018002000

2.0

1.9

1.8

1.7

1.6

1.5

1.4

1.3

1.2

1.1

1.0

0.9

Dailydose(μg)

Ratera

1o

Dose-ResponseCurvefortheRateRa1oofPneumoniaasaFunc1onofICSDose

18

SimilarTimetoModerateorSevereExacerba5onswithWithdrawalandCon5nua5onofICSfrom

TripleTherapy:WISDOMStudy

Weekstoevent

0 6 12 18 24 30 36 42 48 540.00.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Es1m

ated

Proba

bility

Hazardra5o,1.06(95%CI,0.94–1.19)p=0.35byWald’schi-squaretest

ICSwithdrawalICScon5nua5on

No.atriskICScon5nua5on 1243 1059 927 827 763 694 646 615 581 14ICSwithdrawal 1242 1090 965 825 740 688 646 607 570 19

MagnussenHetal.NEnglJMed2014,371:1285-94. 19

DropinTroughFEV1A8erICSWithdrawalfromTripleTherapy:WISDOMStudy

38ml

43ml

06121852

0

-20

-40

-60

-80

Week

Adjusted

meanchan

ge

inFEV

1(ml)

Reducedto500μgReducedto200μgReducedto0μg(placebo)

DailyFlu1casoneDoseinWithdrawalGroup

ICSwithdrawal

ICScon5nua5on

p<0.001

p=0.001

No.atriskICScon5nua5on 1223 1135 1114 1077 970ICSwithdrawal 1218 1135 1092 1058 935

MagnussenHetal.NEnglJMed2014,371:1285-94. 20

Indacaterol/GlycopyrroniumDelayedTimetoFirstExacerba5onvs.Salmeterol/Flu5casone:FLAMEStudy

0 6 12 19 26 32 38 52450102030405060708090100

Prob

abilityofe

xacerba1

on(%

)

Week

IND/GLYgroupSFCgroup

1675 763 535 409 2811679 642 415 313 217

Allexacerba1ons

IND/GLYgroupSFCgroup

1675 1299 1091 948 7111679 1210 975 820 608

Moderateorsevereexacerba1on

16791675

15071530

13891434

13031368

10711138IND/GLYgroup

SFCgroup

Severeexacerba1on

Hazardra5o,0.84(95%CI,0.78–0.91)p<0.001

All

16%riskreduc5on

Hazardra5o,0.78(95%CI,0.70–0.86)p<0.001

ModerateorSevere

22%riskreduc5on

Hazardra5o,0.81(95%CI,0.66–1.00)p=0.046

Severe

19%riskreduc5on

Pa1entsatrisk

Indacaterol/glycopyrronium110/50μgqdSalmeterol/flu5casone50/500μgbid

Analysisoftheperprotocolset(PPS);note:totalrandomizedpopula5oninFLAMEwas3362.AdaptedfromWedzichaJAetal.NEnglJMed2016;374:2222-34. 21

LABA/LAMAnewdevelopments

22

Newstudyshowspoten5albenefitsoflungdefla5ononcardiacfunc5on3RCTscomparingTripletherapyvsLABA/LAMAIndacaterol/glycopyrroniumreceivesHealthCanadaapprovalforincludingreduc5oninexacerba5onasabenefit.

•  Pooledposthocanalysisof3177pa5entsintwoRCTs

•  Pa5entswithbloodeosinophillevels≥2%hadsignificantlylowerratesofmoderate-to-severeexacerba5onswhentreatedwithLABA/ICSvs.LABAmonotherapy

•  Nosignificantdifferencebetweentreatmentsforpa5entswithlevels<2%

RCT=randomizedcontrolledtrialPascoeSetal.LancetRespirMed2015;3:435-42.

Canbloodeosinophilcounthelppredictwhichtherapywillbemosteffec5ve?

DecreasedRatesofModerateorSevereExacerba5onswithLABA/ICSvs.LABAinPa5entswithEosinophilBloodLevels≥2%:PooledAnalysis

ofTwoStudies

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

<2% 2–<4% 4–<6% ≥6%

Flu5casonefuroateplusvilanterol,alldosescombinedVilanterol25μg

Annu

alexacerba1

onra

te(p

a1en

tperyear)

Bloodeosinophilcountgroup

p=0.2804

p=0.0045 p=0.0128

p=0.0020

23

Evidence-BasedNon-PharmacologicalTherapiestoPreventExacerba5ons

AECOPD=AcuteExacerba5onofChronicObstruc5vePulmonaryDiseaseRecommended=level1evidence;Suggested=someevidenceavailable(butnotlevel1)Adaptedfrom:CrinerGJetal.Chest2015;147:894-942.

RECOMMENDED SUGGESTED

•  Pneumococcalvaccine•  Smokingcessa5on•  Educa5onandac5onplan,andcasemanagement

•  Annualinfluenzavaccine•  Pulmonaryrehabilita5on(≤fourweeksa8erhospitaliza5onforAECOPD)

•  Educa5onandcasemanagementwithmonthlyfollowup

24

Whatothertherapiescouldweuse?

Evidence-basedpharmacologicaloraltherapiestopreventexacerba1ons

*AvailableinCanadaasanover-the-counterdrug;**NotavailableinCanada.Recommended=level1evidence;Suggested=someevidenceavailable(butnotlevel1).Adaptedfrom:CrinerGJetal.Chest2015;147:894-942.

SUGGESTED

•  Azithromycin

•  Roflumilast

•  N-acetylcysteine*•  Carbocysteine**

25

Howshouldexacerba5onsbemanaged?

ClinicalTips

•  Pa5entswithpurulentsputumshouldreceivean5bio5ctherapy(par5cularlyiftheyalsohaveincreaseddyspneaand/orincreasedsputumvolume)

•  Systemiccor5costeroidsshouldbeconsideredforpa5entswithworseningdyspnea–  Ifsteroidtherapyisprescribed,shortcourses

(5days)arejustaseffec5veaslongcourses(14days)

26AnthonisenNRetal.AnnInternMed1987;106:196-204;LeuppiJDetal.JAMA2013;309:2223-31;SolerNetal.Thorax2007;62:29-35;Wood-BakerRRetal.CochraneDatabaseSystemicRev2005;1:CD001288.

Forhowlongshouldsystemiccor5costeroidtherapybeprescribed?

REDUCEStudy

36.8 38.335.9 36.7

0

10

20

30

40

50

60

70

80

90

100

Inten5ontotreat Perprotocol

14-daytreatmentwith40mgofprednisonedaily5-daytreatmentwith40mgofprednisonedaily

HR=0.95(95%CI0.70–1.29)

P*=0.006

HR=0.93(95%CI0.68–1.26)

P*=0.005

Shortcoursesarejustaseffec5veaslongercourses

*Pvaluefornon-inferiorityHR=hazardra5oLeuppiJDetal.JAMA2013;309:2223-31. 27

Pa1e

ntse

xperiencingan

othe

rexacerba1

on(%

)

Take-HomeMessages

•  Exacerba5onsdecreasequalityoflife,increasehealthcarecostsandmortality,andacceleratelungfunc5ondecline

•  Pa5entswithsevereCOPD,GERD,symptomsofchronicbronchi5sorahistoryoffrequentexacerba5onsareatincreasedriskoffrequentexacerba5ons

•  Promptandappropriateevalua5onandtreatmentofexacerba5onscanacceleraterecoveryandpostponethenextexacerba5on

•  COPDtherapyandadherencetotherapyshouldbereviewedtoensureitisop5mal

–  Usefulnon-pharmacologicalinterven5onsincludesmokingcessa5on,pulmonaryrehabilita5onandvaccina5on

–  Intermsofinhaledpharmacotherapy,LAMAmonotherapyisausefulfirststep,followedbyLABA/LAMA

•  ICSshouldbereservedforpa5entswithunderlyingasthmaorwithfrequentexacerba5onsdespiteop5malbronchodilatortreatment

–  Thedecisiontotreatneedstobalancedagainsttheincreasedriskofpneumoniaandosteoporosis

28