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HARVARD MEDICAL SCHOOL
AlleviatingtheConfusioninReperfusion:
ManagementofUnstableAngina/NSTEMI
UpdateinInternalMedicine
DuanePinto,MD,MPH,FACCCOPYRIGHT
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Agenda
• RapidRuleOutStrategy
• GeneralGuidelinesandTherapies
• AssessingPatientRisk
• TimingofCatheterization
• NavigatingAnticoagulant/AntiplateletChoices
• NewerChoicesandnewdata
• TheFuture
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EuropeanandUSGuidelinesforNSTEMI
• Firsttimea1Brecommendationforrapidruleout
protocolwithbloodtestat0and1hourusingHS-
Troponinwithadditionaltestingat3-6hrsifthe
first2arenotconclusiveandtheclinicalcondition
isstillsuggestiveofACS
Prospective validation of a 1-hour algorithm to rule-out and
rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243–E252.
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RapidRuleOut
• 1320Patientstreatedaccordingtothe
algorithm
–AMIwasthefinaldiagnosisin17.3%ofpatients.
–786(59.5%)patientswereclassifiedas‘rule-out,’
–216(16.4%)wereclassifiedas‘rule-in’
– 318(24.1%)wereclassifiedtothe‘observational.’
Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243–E252.
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RapidRuleOut
• ThenegativepredictivevalueforacuteMIintherule-
outzonewas99.9%.
• ThepositivepredictivevalueforacuteMIintherule-
inzonewas78.2%.
• Cumulative30-daymortalitywas0.0,1.6,and1.9%in
patientsclassifiedintherule-out,observational,and
rule-ingroups,respectively.
Prospective validation of a 1-hour algorithm to rule-out and rule-in acute myocardial infarction using a highsensitivity cardiac troponin T assay. CMAJ 2015;187:E243–E252.
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ImmediateManagement
•Thehistory,physicalexamination,12-leadECG,and
initialcardiacbiomarkertestsshouldbeintegrated
•Assignpatientswithchestpaininto1of4categories
–Noncardiacdiagnosis
–Chronicstable angina
–Possible ACS
–Definite ACS
6
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UniversalDefinitionofMI
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UniversalDefinitionofMI
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Goals for the Management of Non-ST Elevation
Acute Coronary Syndromes
Unstable Angina
Prevent immediate risk of MI and improve long-term outcome
Non-STEMI
Minimize extent of MI to improve long-term outcome
Prevent repeat MI to improve long-term outcomeCOPYRIGHT
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GeneralTherapies
• AntiIschemicTherapy&
PainControl
–Oxygen
–Nitrates
• IfSBP>100without
CHF
–Morphine
• OralBetaBlockade
within24hrsUnlessHF,Lowoutput state,
PR>0.24,HeartBlock,Active
Asthma/ReactiveAirway
Disease
• ACE-Iwithin24hrsif
HForLVEF<=40%UnlessBP<100or>30mmHg
belowbaseline
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Aspirin in the Treatment of ACS
Wallentin LC, et al. JACC 1991;18:1587-
93.
0.00
0.05
0.10
0.15
0.20
0.25
0 3 6 9 12
Months
Pro
bab
ilit
yo
f D
eath
or
MI
Placebo
Aspirin 75 mg
Risk ratio 0.5295% CL 0.37-0.72
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Beta Blockers
It may be harmful to administer intravenous beta blockers to UA/NSTEMI patients
who have contraindications to beta blockade, signs of HF or low-output state, or
other risk factors* for cardiogenic shock.
*Risk factors for cardiogenic shock (the greater the number of risk
factors present, the higher the risk of developing cardiogenic
shock):
1.age >70 years
SBP <120 mmHg
2.sinus tachycardia >110 or heart rate >60
3.increased time since onset of symptoms of UA/NSTEMI.
Chen ZM, et al. Lancet 2005;366:1622–32.
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GoalsforTherapyDuringNSTEMI
Patientriskdictatesmanagement
• Goals:
–UnstableAngina:PreventProgressiontoInfarct
–NSTEMI:MinimizeInfarctSizeandRecurrentMI
• Therapeuticagents
–Anticoagulants
–AntiPlatelets
• InvasiveManagement
–Angiographytofurtherclarifyrisk
– Revascularizationtoarrestthrombusprogression
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I’mConfused
NSTEMI
Early
Invasivevs.
SelectiveInvasive
Which
Anticoagulant?
•LMWH
•UFH
•DTI
WhichAntiplatelet?
•Clopidogrel
•Prasugrel
StartMedsUpstreamvs.InCath
Lab?WhichStent?
•DrugElutingvs.Bare
MetalStent
WhatifPt.needsaCABG?
600mgvs.300mg
Clopidogrel?
WhatDoseofASA?
LMWH=Low Molecular Weight Heparin
UFH= Unfractionated Heparin
DTI= Direct Thrombin Inhibitor
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EARLYINVASIVESTRATEGY
WHOANDWHEN?
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TIMI
Risk
Score
All-CauseMortality,NeworRecurrentMI,orSevere
RecurrentIschemiaRequiringUrgentRevascularization
Through14DaysAfterRandomization%
0-1 4.7
2 8.3
3 13.2
4 19.9
5 26.2
6-7 40.9
TIMI Risk Score
Antman EM, et al. JAMA 2000;284:835–42. Copyright © 2000, American Medical Association. All
Rights reserved. The TIMI risk calculator is available at www.timi.org.Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Table 8.
TIMI = Thrombolysis in Myocardial Infarction.
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MortalityandtheTIMIRiskScore
JAMA 2000;284:835–42 (159).
NSTEMI is generally caused by a partially occlusive, platelet-rich
thrombus in a coronary artery
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RelativeRiskforAll-CauseMortality:EarlyInvasivevsSelectiveInvasiveTherapy
Bavry A, et al. J Am Coll Cardiol.
2006;48:1319-1325.
692
121515
130
60132102
63937
1293
246745
Follow-up,MonthsConservativeInvasive
Deaths, n
Study
FRISC-II
TRUCS
TIMI-18
VINO
RITA-3
ISAR-COOL
ICTUS
Overall RR (95% CI) 0.75 (0.63-0.90)
0.1 1 10
Favors Early Invasive
Therapy
Favors Conservative
Therapy
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Timetocatheterization(hrs)
EARLY LATE
FRISC2(1999) 96 408
TRUCS(2000) 48 120
TIMI-18(2001) 22 79
VINO(2002) 6 1464
RITA3(2002) 48 1020
ELISA(2003) 6 50
ISAR-COOL(2003) 3 86
ICTUS(2005) 23 283
TIME-ACS(2009) 14 50
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PrimaryOutcome
Death,MI,orStroke
Days
Cu
mu
lati
ve H
azard
0.0
0.0
20.0
60.1
0
0 30 60 90 120 150 180
Death/MI/Stroke at 180 days
Early
No. at Risk
Delayed
Early
1438 1328 1269 1254 1234 1229 1211
1593 1484 1413 1398 1391 1382 1363
Delayed
HR 0.8595% CI 0.68-1.06
P= 0.15
TIMACS
N Engl J Med. 2009 May 21;360(21):2165-75.
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ESCGuideline2016
• ImmediateInvasiveStrategywithin2hoursforveryhigh
riskpatients
–Shock,severeheartfailure,arrhythmia,ongoingchestpain
• Earlyinvasivewithin24hoursforhighrisk
• Invasive(within72hours)forintermediateriskCOPYRIGHT
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Summary
• RiskstratifypatientswithUA/NSTEMIusingsimpleclinical
scores(TIMI,GRACE)
• Selectforfurtherinvasivework-upthosewhoareatmoderate
andhighriskforischemiccomplications
• Catheterizationshouldbeurgentbutnotemergentforhighrisk
individuals
• Lowriskindividualsshouldhavenoninvasivework-upfirst
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MEDICATIONSFORUA/NSTEMI
PLATELETSANDTHROMBUS
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Questions
• Whichpatientsformoreaggressiveantiplateletmedications?
• Whentoadminister(pre-cath,atcath,post-cathetc)?
• Whichones(oral,IVorboth)?
• Neweragents?
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EmbolisminNSTEMI
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WHICHORALAGENTBESIDESASPIRIN?
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P2Y12 Inhibitors
Clopidogrel Prasugrel Ticagrelor
Class Thienopyridine Thienopyridine Triazolopyrimidine
Bindingto
ReceptorIrreversible Irreversible Reversible
ActivationProdrug,limited
bymetabolisation
Prodrug,notlimited
bymetabolisationActivedrug
Nonresponders Yes No No
OnsetofEffect 2–4h 30min 30min
DurationofEffect 3–10days 5–10days 3–4days
Withdrawal
Before
MajorSurgery5days 7days 5days
HammCW,etal.EurHeartJ.2011;32:2999–3054.www.escardio.org/guidelines.
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ClopidogrelDuringUA/NSTEMI
CURE investigators. N Engl J Med. 2001;345:494-502.
CV death, MI, stroke (%)
RR = 0.80P<.001
Days After Enrollment
0
4
8
12
0 100 200 300 400
9.3
11. 4
Placebo (n=6303)
Clopidogrel (n=6259)COPYRIGHT
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0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32
(1.03-1.68)P=0.03
Prasugrel
Clopidogrel1.8
2.4
138
events
35
events
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167
Wiviott et al NEJM 2007
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32
TRITON-TIMI38:NetClinicalBenefit
BleedingRiskSubgroups
Post-hocanalysis
OVERALL
≥ 60 kg
< 60 kg
< 75
≥ 75
No
Yes
0.5 1 2
PriorStroke / TIA
Age
Wgt
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = .006
Pint = .18
Pint = .36
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
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ESCGuideline2016
• ClassIII
indicationfor
Prasugrel
beforeanatomy
isknownbased
onthe
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No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,560
8,678
8,405
8,520
8,177
Days after randomisation
6,703
6,796
5,136
5,210
4,109
4,191
0 60 120 180 240 300 360
6
5
4
3
2
1
0
7
Cu
mu
lati
ve i
ncid
en
ce (
%)
Clopidogrel
Ticagrelor
5.8
6.9
8,279
HR 0.84 (95% CI 0.75–0.95), p=0.005
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Myocardial infarction Cardiovascular death
Cu
mu
lati
ve i
ncid
en
ce (
%)
Ticagrelor:PLATO
N Engl J Med. 2009 Sep 10;361(11):1045-57. Epub 2009 Aug 30.
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WHENTOGIVETHEORALAGENTS?
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TimingofClopidogrelLoadingInUSPractice
Dean BB et al. Am J Health-Syst Pharm 2010; 67: 1430-7.
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Recommendation COR LOE
Amsterdam E, et al. Circulation. 2014.
Post-Discharge:Aspirinindefinitely I AAspirin81mginpreferencetohigherdoses IIa B
Iftreatedmedically(norevascularization):clopidogrelorticagreloraddedtoaspirinandcontinuedforupto12months
I B
IftreatedwithPCI:clopidogrel,prasugrel,orticagreloraddedtoaspirinandcontinuedatleast12months
I B
Ticagrelor(PCIormedRx)orprasugrel(PCI)inpreferencetoclopidogrel IIa B
TherapyatthetimeofPCI:P2Y12at thetimeofPCI:clopidogrel(LOE=A),prasugrel(LOE=B),ticagrelor(LOE=B,)orGPI(LOE=A)
I B
Prasugrelorticagrelorinpreferencetoclopidogrelinpatientsundergoingcoronarystenting
IIa B
PrasugrelpotentiallyharmfulaspartofDAPTinpatientswithapriorhistory ofCVAand/orTIA
III:Harm
B
InitialTherapy:Aspirin(160-325mg)assoonaspossibleafterhospitalpresentation,followedby81mgdaily
I A
AP2Y12 inhibitor(clopidogrelorticagrelor)inadditiontoaspirintoallpatientswithNSTE-ACSwithoutcontraindications
I B
Ticagrelorinpreferencetoclopidogrel IIa B
2014 ACCF/AHA Select Recommendations for Oral Antiplatelet Agents with NSTE-ACS
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Preloading May Not Actually Be Preloading
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Circulation
Volume 130(21):1904-1914November 18, 2014
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CangrelorNowApprovedforPCIDirect platelet P2Y12 receptor antagonist
●ATP analogue MW=800 Daltons
●Parenteral administration
●Rapid inhibition (> 90%) at 4 mg/kg/min after a weight-
based bolus
●Full recovery of platelet function in <60 minutes
●t 1/2 - 3- 5 minutes
●Putative metabolism by endothelial-associated
ectonucleotidases/CD 39
N N
N N
NH
SCF3
OHOH
OO
PO
OPP
OO
OCl
Cl
OO
O
S
4Na
+
Meadows TA, Bhatt DLCirc Res 2007;100:1261-75; Akers J Clin Pharmacol. 2010;50:27-35; Steinhubl Thromb Res. 2008;121:527-34.
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Summary:WhattoDoforOralandIntravenousAntiplatelets
• ASA325mgorally,uncoated,chew-OK
• Clopidogrel 600mg,TicagrelorOKespifyouthinkwillnotneedCABG
• PrasugrelOKbutNO ifpriorTIA/Strokeandcautionage>75,weight<60kg
• ASA81mgadaywithticagrelor
• GPI:OKtowaitforcathlabbutstartiffailabove(recurrentchestpain,ECGchanges)
• Cangreloranoption incathlabforpatientswithunknownbleeding risk,inadequate
oralantiplatelet therapyorpossibility ofurgentCABGCOPYRIGHT
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Anticoagulantchoices
Unfractionated heparin
LMW Heparin
BivalirudinFondaparinux
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SummaryAnticoagulants
• UnfractionatedHeparin– HITRisk,NeedtoTitrate,VariableResponse,plateletactivation,inferioroutcomes
• LMWH– Mainadvantage iseaseofadministration.
– Notcath labfriendly.
– Avoidifthinkgoing toCABG
– Avoidinrenal failure
• Fondaparinux– Goodformedical management esp.ifbleeding risk
– Notfavoredifinvasivemanagement selected
• Bivalirudin– Notaplatelet activator
– Lessbleeding andsimilar outcomeswhencompared toheparin pairedwithIVantiplatelets
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GuidelineRecommendation:AccessSite
• Europeans
–RadialPreferredinexperiencedcenters
•Americans
–RadialanoptionCOPYRIGHT
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Rate Ratio 0.83; 95% CI, 0.73 to 0.96; p=0.0092
11.7%
9.8%
NNTB: 53FemoralRadial
Primary EP: NACE
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Summary
• RiskstratifypatientswithUA/NSTEMI usingsimple clinical scores(TIMI,GRACE)
• Select forfurther invasivework-upthosewhoareatmoderateandhighriskfor
ischemic complications
• Catheterization shouldbeurgentbutnotemergent forhighriskindividuals
• Lowriskindividuals shouldhavenoninvasivework-upfirst
• Thinktwiceaboutoxygenandmorphine routinely
• Oralagentsmaynotbeonboardifinlabrapidly
• Radialpreferred
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References:ESCandAmericanGuidelines
• RoffiM,etal.EurHeartJ2016;37:267–315.
• Amsterdam EA.Circulation 2014;130:2354–2394.
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