presenter disclosure - npac-aiipc
TRANSCRIPT
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