COP Management of Unstable Angina/NSTEMI YRIGHT - primarycare.tips · HARVARD MEDICAL SCHOOL Rapid Rule Out •1320 Patients treated according to the algorithm –AMI was the final

HARVARD MEDICAL SCHOOL

AlleviatingtheConfusioninReperfusion:

ManagementofUnstableAngina/NSTEMI

UpdateinInternalMedicine

DuanePinto,MD,MPH,FACCCOPYRIGHT


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


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


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


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

ACCOASTTrialCOPYRIGHT


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


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


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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Documents

COP Management of Unstable Angina/NSTEMI YRIGHT - primarycare.tips · HARVARD MEDICAL SCHOOL Rapid Rule Out •1320 Patients treated according to the algorithm –AMI was the final