4/5/2017 Chemotherapy‐Related Cardiac Dysfunction & How a Cardiology‐Oncology Clinic Can Help!

4/5/2017
1
Chemotherapy‐RelatedCardiacDysfunction
&
HowaCardiology‐OncologyClinicCanHelp!
April22,2017
MariaAnwar, BScPharm,ACPR
[email protected]a
KeyLearningObjectives
•Toprovideabriefbackgroundaboutcardio‐oncology
•Todefineofchemotherapy‐relatedcardiacdysfunctionandreview
theincidence,mechanismandrisksassociatedwithvariousagents
•Tohighlightanapproachtocareandpatientriskassessment
•ToreviewtheCanadianCardiovascularSocietyGuidelinesforthe
EvaluationandManagementofCardiovascularComplicationsof
CancerTherapyandselectclinicaltrialsincluding:strategiesfor
prevention,detection&surveillanceandtreatmentof
chemotherapy‐relatedcardiacdysfunction
•TosharetheSouthHealthCampus(SHC)Cardio‐OncologyClinic
servicemodel
•Todiscussimplicationsforpharmacistsandpatients
Cardio‐Oncology
•Emergingsubspecialtythataimsto“optimizecardiaccarefor
cancerpatients”
•Increasingratesofbothcancersurvivalandmorbidity&
mortalityfromcardiovascularcauses
•Sharedpopulation&riskfactors
•Cardiovascularhealthlinkedtoimprovedcanceroutcomes
•Multidisciplinarycollaboration
•“CureCancer,SaveHearts”
CJC2016;831‐841 CanadianCardio‐OncologyNetwork(CCON)http://cardiaconcology.ca/
Cancer
Cardiac
Status
Cancer
Treatment
Patient
Cardiology
Team
Oncology
Team
Family&Friends
SupportServices
Resources
Community
Chemotherapy‐RelatedCardiacDysfunction
Stage Definition LVEF Symptoms
AAthighriskforHF No cardiacdysfunction No
B1 OccultLVdysfunction LVEF>53%, abnormalstrain
and/orcardiacbiomarkers
No
B2 OvertLVdysfunction LVEF<53% No
C SymptomaticHF,
responsive toconventional
therapy
LVEF <53% Yes
D SymptomaticHF,
unresponsive toconventional
therapy
LVEF <53%(usuallylower)Persistent
NYHAIV
Cancer
Treatment
Adaptedfrom:CJC2016;891‐899
Anthracyclines
•Mechanism:
–EnternuclearDNAimpairedprotein
synthesis&productionofreactiveoxygen
species
–BindtoDNAandtopoisomeraseII‐betain
cardiacmyocytesmyocardialdamage&
celldeath
–Cumulativedoserelated
•Acute(<1%):
–Immediatelyaftertransfusion
–TransientLVdysfunction,supraventricular
arrhythmiasandECGchanges
–Usuallyreversiblemyocyteinjurycan
evolveintoearlyorlatecardiotoxicity
•Early(1.6–2.1%)
–Withinfirstyearoftreatment
–Canbeasymptomatic,continuous
progressivedeclineinLVEF
–Usuallyirreversiblegoodfunctional
recoveryifdetectedandtreatedearlywith
HFmedications
•Late(1.6–5%)
–Afterfirstyearoftreatment
–DeclineLVEFfollowedbyclinical
decompensation
–Usuallyirreversible
CJC2016;831‐841 EHJ2016;37:2768‐2801 Circ HeartFail2016;e002661
Cancer
Treatment

4/5/2017
2
HER2‐Inhibitors
•Incidence:trastuzumab(1.7‐
20.1%),pertuzumab (0.7‐1.2%),
lapatinib (0.2‐1.5%)
•Mechanism(trastuzumab):binds
tohumanepidermalreceptor2
(HER2)proteinoncardiac
myocyteinhibitingErbB2‐ErbB4
signalingdisablescellgrowth
pathwayactivatedduringtimes
ofmyocardialstress
myocardialdysfunction
•Features:
–Usuallyappearsduringtreatment
–Generallynotdoserelated
–Likelyreversible
–Concomitantorprevioususeof
anthracyclinesorpaclitaxel
increasesrisk
CJC2016;831‐841 EHJ2016;37:2768‐2801 BJC2009;684‐692Circ HeartFail2016;e002661
Cancer
Treatment
OtherAgents
Alkylatingagents
•Incidence:cyclophosphamide(7‐28%),
ifosfamide (0.5‐17%)
•Mechanism:directendothelialinjury
cardiomyocytedamage andedema
•Features:usuallyoccurswithin1‐14days
afteradministration,likelysinglehigh‐dose
related,maybereversibleorirreversible
Antimicrotubule agents
•Incidence:docetaxel(2.3‐13%),paclitaxel
(<1%)
•Mechanism:impaircelldivision,interfere
withmetabolism&excretionof
anthracyclines(potentiaterisk)myocyte
damage
VEGFInhibitors
Incidence:bevacizumab(1.6‐4%),sunitinib
(2.7‐19%),sorafenib (4‐8%),dasatinib (2‐
4%),imatinib (0.2‐2.7%)
Mechanism:inhibitionofvascular
endothelialgrowthfactorreceptor
mediatedangiogenesismitochondrial
damage
Features:generallyreversible
Proteasomeinhibitors
Incidence:bortezomib (2‐5%)
Mechanism:impairedproteasome
mediatedmaintenanceofcardiomyocytes
myocardialdysfunction
Cancer
Treatment
CJC2016;831‐841 EHJ2016;37:2768‐2801 Circ HeartFail2016;e002661
ApproachtoCare
1. Identifypatientsatincreasedriskofdevelopingchemotherapy‐
relatedcardiacdysfunction
2. Optimizemanagementofcardiovascularriskfactorsandco‐
morbidities
3. Monitorpatientswhilereceivingchemotherapy
4. Monitorpatientsaftercompletionofchemotherapy(surveillance)
5. Managepatientsthatexperiencechemotherapy‐relatedcardiac
dysfunctionwithmedicationsandlifestylerecommendations
Patient
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
RiskAssessment
1. History
2. Physicalexam
3. EvaluationofLVfunctionECHO,CMR,
MUGA
4. Cardiacbiomarkerstroponin,NT‐proBNP
PatientFactors:
•Advancedoryoungage
•Female(anthracycline)
•Hypertension
•Diabetes
•Dyslipidemia
•Obesity
•Smoking
•Familyhistory
•Sedentary
CardiacFactors:
•Heartfailure
•Leftventriculardysfunction
•Coronaryarterydisease
•Moderateorseverevalvular heartdisease
•Arrhythmias
•Cardiomyopathy
•Cardiacsarcoidosisinvolvingmyocardium
CancerTreatmentFactors:
•Highcumulativedoseofanthracycline
•Timingofadministrationofanthracyclineandother
chemotherapy(ie.trastuzumab,cyclophosphamide,
paclitaxel)
•Prioranthracyclineuse
•Priororcurrentradiationtherapyinvolvingthe
heart
•Curativevspalliativeintent
Cancer
Cardiac
Status
Cancer
Treatment
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
CCS Guidelines: Risk Assessment
“We recommend evaluation of traditional cardiovascular risk factors and
optimal treatment of cardiovascular disease, as per current CCS
guidelines, be part of routine care for all patients before, during, and
after receiving cancer therapy
(Strong Recommendation, Moderate-Quality Evidence).
We recommend that patients who receive potentially cardiotoxic cancer
therapy undergo evaluation of LV ejection fraction (LVEF) before
initiation of cancer treatments known to cause impairment in LV
function
(Weak Recommendation, Moderate-Quality Evidence).”
CJC2016;831‐841
Prevention
•Treatriskfactorsandco‐
morbidities
•Positivehealth‐promoting
behaviour
•Cancertreatmentconsiderations
–Lesscardiotoxic agents
–Limitanthracyclinecumulative
doses
–Administrationtechnique&
formulation
–Minimizecardiacirradiation
•Cardioprotective medications
–ACEI/ARB
–BB
–Statins
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
Cardiac
Status
Cancer
Treatment

4/5/2017
3
PRADA
DRCT,PC,DB,2x 2 factorial,ITT,singlecenterinNorway
PAdultwomenwithearlybreast cancerreceivingadjuvantchemotherapywith
5‐fluorouracil,epirubicin andcyclophosphamide(FEC)
LVEF>50%
Nopriorcardiacdisease
~22%receivedtrastuzumaband~80%taxanes afterFEC
I
C
Candesartan32mgdaily +metoprololsuccinate100mgdaily(n=30)
Candesartan32mgdaily+placebo(n=32)
Metoprololsuccinate+placebo(n=32)
Placebo+placebo(n=32)
Initiatedpriortochemotherapy&continued10–61weeks(duringadjuvanttreatmentperiod)
OChangeinLVEFfrombaselinetocompletionofadjuvanttherapybyCMR:
‐0.6%candesartan+metoprolol(P=0.075comparedtoplacebo‐placebo)
‐0.9%candesartan+placebo(P=0.025comparedtoplacebo‐placebo)
‐2.5%metoprolol+placebo(P=0.71comparedtoplacebo‐placebo)
‐2.8%placebo+placebo(control)
Secondary=Nosymptomatic HF
NosignificantchangeinRVEF,LV GLS,diastolicfunction,troponinorBNPlevels
EHJ2016;1671‐1680
MANTICORE101‐Breast
DRCT,PC,DB, ITT,2centersinCanada
PAdultwomenwithHER2‐postiveearlybreast cancerreceivingadjuvanttrastuzumabtherapy
~67‐87%docetaxel,carboplatinandtrastuzumab(TCH)
~13‐30%5‐fluorouracil,epirubicin andcyclophosphamidefollowedbydocetaxel andtrastuzumab(FEC‐DH)
LVEF>50%
Nopriorcardiacdisease
IPerindopril8mg(n=33)orbisoprolol 10mg(n=31)
Initiatedwithin7daysoftrastuzumab&continuedduringadjuvantperiod(usually12months)
CPlacebo(n=30)
OPrimary =changeinindexedLVenddiastolicvolume(LVEDVi inml/m2)frombaselinetocompletionof
trastuzumabtherapy:
+7perindopril,+8bisoprolol and+4placebo(P=0.36)
Secondary=changeinLVEFfrombaselinetocompletionoftrastuzumabtherapybyCMR:
‐1%bisoprololvs‐ 3%perindoprilor–3%placebo(P=0.001)
CTRCD=>10percentagedeclineinLVEFto<53%:
3%perindoprilor3.2%bisoprololvs20%placebo(P=0.02 post‐cycle4)(NSpost‐cycle17)
Clinicalcardiotoxicity=>7dayinterruptionintrastuzumabduetoLVdysfunction
9%perindoprilor9.7%bisoprololvs30%placebo(P=0.03)
JCO2017;870‐878
Atorvastatin
DRCT,singlecentre
Follow up:6monthafterchemotherapy
PPatientswithnon‐Hodgkinlymphoma,multiplemyeloma, leukemiatreatedwithregimens
containingdoxorubin oridarubicin
Nopriorcardiacdisease
Regardlessoflipidlevels
IAtorvastatin40mgdaily(n=20)
Initiated priortochemo&continuedx6months
CControl(n=20)
OPrimary =LV systolicimpairmentdefinedasLVEF<50%byECHO:
notstatisticallysignificant
1patientinatorvastatingroup,5patientsincontrolgroup
Secondary=MeanchangeLVEF6monthsafterchemotherapy:
+1.3%atorvastatin vs‐7.9%control(P<0.001)
JACC2011;988‐989
EvidenceforPrevention
Strengths:
•RCTdata
•Lowtomoderatedosesof
anthrayclines
•Withorwithouttrastuzumab
•EndpointswithimagingdatafromCMR
•PrimarypreventionofLVEFdecline
mayreducelong‐termriskofcardiac
dysfunction
Limitations:
•Smallsamplesizes
•Heterogeneity
•Lowcardiacrisk
•Variationincombinationandduration
ofcardioprotective medication
regimens
•Differentsurrogateprimaryendpoints
•Extentofclinicalbenefit?
•Exposuretopotentialsideeffects&
duginteractions
•Cost
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
Cardiac
Status
Cancer
Treatment
CCS Guidelines: Prevention
“We suggest that in patients deemed to be at high risk for
cancer treatment-related LV dysfunction, an ACE inhibitor
or angiotensin receptor blocker, and/or beta-blocker, and/or
statin be considered to reduce the risk of cardiotoxicity.”
Weak Recommendation
Moderate-Quality Evidence
CJC2016;831‐841
Detection&Surveillance
•Closemonitoring&early
detection
•SerialdeterminationofLV
function
–Frequency
–LVEF
•Imagingmodality
•Cardiacbiomarkers
•Localinstitutionalprotocols
•Clinicalassessment
Bottomline
Individualizedmonitoringstrategy
tailoredbasedonriskassessment,
signs&symptomsofHF&resultsof
cardiacimagingandbiomarkers
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801

4/5/2017
4
SHCCardio‐OncologyProtocol
AnthracyclineBasedChemotherapy:
BaselineCMRprechemo
RepeatCMRevery3monthsduringtreatment
AnnualCMRfromchemostartdatefor
5years
NT‐proBNP/troponinwithimagingunlessMDspecifies
otherwise
UsestrainECHOorMUGAifCMRcontraindicated
ConsiderCardiologyConsult:
LVEFabsolutedrop>10%,
LVEDVi incre a seof2SD,
NT‐proBNP>agedeterminedlimit,
troponin(hs TnT)>50ng/L
AdjuvantHerceptinorKadcyla
(TrastuzumabBased)Treatment:
BaselineCMRprechemo
RepeatCMRevery3months
duringtreatment
Surveillanceendswhentreatmentcompleted
NT‐proBNP/troponinunlessMDspecifiesotherwise
UsestrainECHOorMUGAifCMRcontraindicated
ConsiderCardiologyConsult:
LVEFabsolutedrop>10%,
LVEDVi incre a seof2SD,
NT‐proBNP>agedeterminedlimit,
troponin(hs TnT)50ng/L
ApprovedMay12,2016
CCS Guidelines: Detection
“We recommend the same imaging modality and method be used to determine
LVEF before, during, and after completion of cancer therapy
(Suggestion, Low-Quality Evidence).
We suggest that myocardial strain imaging be considered a method for early
detection of subclinical LV dysfunction in patients treated with potentially
cardiotoxic cancer therapy
(Suggestion, Low-Quality Evidence).
We suggest that serial use of cardiac biomarkers (eg, BNP, troponin) be
considered for early detection of cardiotoxicity in cancer patients who receive
cardiotoxic therapies implicated in the development of LV dysfunction
(Weak Recommendation, Moderate- Quality Evidence).”
CJC2016;831‐841
Treatment
•Prompttreatment
•Riskvsbenefitassessment
•Cancertreatment
considerations
–Holdingmedications
–Dosereductions
–Switchingtolesscardiotoxic
agents
•Heartfailuretherapy
–ACEI/ARB
–BB
–MRA
–Diuretics/symptom
management
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
Cardiac
Status
Cancer
Treatment
EnalaprilorEnalapril+Beta‐Blocker
DProspective,singlecentreinMilanbetweenJune1,1995andMay31,2014
PAdult patients(n=2625)
Mainlynon‐HodgkinlymphomaandbreastcancerreceivinganthracyclinesLVEF>50%
Nohighdoseanthracyclineortrastuzumab
IEnalapril(before1999)orenalapril +carvedilol/bisoprolol(after1999)
Initiatedpromptlyupondetection,up‐titratedtomaxtolerateddoses
Followup:ECHOatbaseline,q3moduring&thefirstyearfollowingtreatment,
q6moduringthefollowing4yearsthenannually(medianfollowup=5.2years)
OPrimary =timeofoccurrenceofcardiotoxicityreductioninLVEF>10pointsfrombaselineand
<50%byECHO:
9%(n=226)developedcardiotoxicity(dose‐dependent)
mediantime=3.5monthsafterlastdoseofanthracycline(98%withinthefirstyear)
Secondary:
82%(n=185)recoveredfromcardiotoxicityaftertheinitiationofHFtreatment
71%(n=160)partialrecovery(LVEFincrease>5pointsand>50%,noHFsymptoms)
11%(n=25)fullrecovery(LVEFincreasetothebaseline)
18%(n=41)didnotrecoverandweremorelikelytobeinNYHAIII‐IV,lesstoleranttocardiac
medications,lowerLVEFbeforeHFtherapyandhadahigherincidenceofadversecardiacevents
Circ 2015;1981‐1988
EnalaprilorEnalapril+Carvedilol
JACC2010;213‐220
DProspective,singlecentreinMilanbetweenMarch1,2000andMarch1,2008
PAdult patientswhoreceivedanthracyclines(n=201)mostlydoxorubicin&epirubicin
Mainlynon‐Hodgkinlymphoma,breastcancerandothertumors
LVEF<45%+/‐HFsymptomsandexcludedothercausesforcardiacdysfunction
IEnalapril(if <5mg/day)orenalapril +carvedilol
Initiatedwithin4months(median)andup‐titratedtomaximumtolerateddoses
Followup:ECHOatbaseline,q1mox3months,thenq3moforthefirst2followingyearsthenq6mo
untiltheendofstudy(medianfollowup=3years)
OPrimary =LVEFresponsetoHFtherapy
1. 42%(n=85)fullresponse(LVEF> 50%)– 13%NHYAIIIorIV,LVEF41%priortoHFtreatment,75%
onACEI&BB,HFtreatmentinitiatedwithin2months,completereversalwithin7months
2. 13%(n=26)partialresponse(LVEFincreased>10pointsbutremained<50%)
69%NHYAIIIorIV,LVEF28%priortoHFtreatment,50%onACEI&BB,69%diuretics,
HFtreatmentinitiatedwithin2month
3. 45%(n=90)nonresponders(LVEFincreased<10andremained<50%)
27%NHYAIIIorIV,LVEF38%priortoHFtreatment,54%onACEI&BB,
50%diuretics,HFtreatmentinitiatedwithin17months,morecardiacevents
CJC2016;296‐310

4/5/2017
5
EvidenceforTreatment
Strengths:
•Prospectivetrials
•Heartfailureevidence‐basedACEIand
betablockers
•Earlydetectionandprompttreatment
mayresultinrecoveryofheart
function
Limitations:
•BlindedRCTslacking
•Variousdefinitionsofcardiac
dysfunction&responsetotherapy
•Heterogeneity
•Mainlypatientswithanthracycline‐
relatedcardiacdysfunction
•Approachnotindependentlyvalidated
•Idealcardiacmedicationtreatment
regimenandinitiationoftherapy?
•Optimaldurationoftherapy?
Cardiac
Status
Cancer
Treatment
CJC2016;831‐841 JCO2017;893‐911 EHJ2016;37:2768‐2801
CCS Guidelines: Treatment
“We recommend that in cancer patients who develop clinical HF or an
asymptomatic decline in LVEF (eg, > 10% decrease in LVEF from baseline or
LVEF < 53%) during or after treatment, investigations, and management follow
current CCS guidelines. Other causes of LV dysfunction should be excluded
(Strong Recommendation, High-Quality Evidence).
We suggest that patients at high risk of cancer therapy-related cardiovascular
disease or patients who develop cardiovascular complications during cancer
therapy (eg, > 10% decrease in LVEF from baseline or LVEF < 53%) be
referred to a cardio-oncology clinic or practitioner skilled in the management of
this patient population, for optimization of cardiac function and consideration
of primary or secondary prevention strategies
(Suggestion, Low-Quality Evidence).”
CJC2016;831‐841
SHC Cardio‐OncologyClinic
Mandate:
•Consultativeserviceforadultpatientscurrentlyunder
thecareofacancerspecialist
•Aimtohelppatientsremainontheircancertreatment
andprotecttheirheart
•Referralcriteria:
–Baselineassessmentandsurveillancepriorto
initiatingchemotherapy
–Cardiacsurveillancefor5yearsaftercompletion
ofanthracycline‐basedchemotherapytreatment
–Cardiacsymptomsorconcernsduringorpost
cancertreatment
–Cardiacclearanceforstemcelltransplant
–Cardiacamyloidosis
–Cancersurvivors>18yearsofage,previously
followedbytheAlbertaChildren’sHospitaland
treatedwithanthracyclinebasedchemotherapy
orradiationtothechest
ServiceDeliveryModel:
•Referraltriage:
–Urgent(within72hours)
–Semi‐urgent(within5businessdays)
–Routine(within3weeks)
•Collaborativepractice
•Patientandfamilyeducation
•Riskassessment
•Surveillance
•Managementofcardiaccomplicationsdueto
cancertreatment
•Teleph o n e andfacetofacevisits
AnwarM,SheppardC.CAPhOConference2017Poster
Cancer
Cardiac
Status
Cancer
Treatment
ImplicationsforPharmacists
1. Whodowetreat?
2. Howdowetreatthem?
3. Whatismostimportant
tothepatient?
4. Research&evidenceis
growing
5. Careisevolving
Cancer
Cardiac
Status
Cancer
Treatment
Patient
Puttingitalltogether…
Circ 2012;2749‐2763
Acknowledgments
SHCCardio‐OncologyClinicpatients&staff
ChristinaSheppard
GloriaKinsella
DebBosley
Dr.BrianClarke