Guidelines for the Management of Non Guidelines for the Management of Non STSTAcute Coronary SyndromesAcute Coronary Syndromes

Nathaniel Niles, MDNathaniel Niles, MDAssociate Professor of MedicineAssociate Professor of Medicine

Dartmouth-Hitchcock Medical CenterDartmouth-Hitchcock Medical Center

Evidence-Based Medicine:Evidence-Based Medicine:What’s the Problem?What’s the Problem?

““There is an unsettling truth about the practice of There is an unsettling truth about the practice of

medicine. …study after study shows that few medicine. …study after study shows that few

physicians systematically apply to everyday treatment physicians systematically apply to everyday treatment

the scientific evidence about what works best.”the scientific evidence about what works best.”

Millenson, ML. Demanding Medical Excellence: Doctors Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997and Accountability in the Information Age. 1997Millenson, ML. Demanding Medical Excellence: Doctors Millenson, ML. Demanding Medical Excellence: Doctors and Accountability in the Information Age. 1997and Accountability in the Information Age. 1997

Updated ACS GuidelinesUpdated ACS GuidelinesWeighing the EvidenceWeighing the Evidence• 1994 version was starting point1994 version was starting point

• Literature searches Literature searches

• Evidence tablesEvidence tables

• Revisions in 2000 and October 2002 added more current Revisions in 2000 and October 2002 added more current

reportsreports

• Weight of evidence grades:Weight of evidence grades:

== Data from many large, randomized trialsData from many large, randomized trials

== Data from fewer, smaller randomized trials, careful Data from fewer, smaller randomized trials, careful

analyses of nonrandomized studies, observational registriesanalyses of nonrandomized studies, observational registries

== Expert consensusExpert consensus

II IIaIIa IIbIIb IIIIII

Updated GuidelinesUpdated GuidelinesClasses of RecommendationsClasses of Recommendations

Intervention is useful and effectiveIntervention is useful and effective

Evidence conflicts/opinions differ but Evidence conflicts/opinions differ but leans towards efficacyleans towards efficacy

Evidence conflicts/opinions differ but Evidence conflicts/opinions differ but leans against efficacyleans against efficacy

Intervention is not useful/effective and Intervention is not useful/effective and may be harmfulmay be harmful

Intervention is useful and effectiveIntervention is useful and effective

Evidence conflicts/opinions differ but Evidence conflicts/opinions differ but leans towards efficacyleans towards efficacy

Evidence conflicts/opinions differ but Evidence conflicts/opinions differ but leans against efficacyleans against efficacy

Intervention is not useful/effective and Intervention is not useful/effective and may be harmfulmay be harmful

Annual Patient Admissions for Annual Patient Admissions for Acute Coronary SyndromesAcute Coronary SyndromesAnnual Patient Admissions for Annual Patient Admissions for Acute Coronary SyndromesAcute Coronary Syndromes

1.4 MMNon-ST elevation ACS

0.6 MMST-elevation MI

~ 2.0 MM patients admittedto CCU or telemetry annually

Prognosis in Non STPrognosis in Non STACSACS

PURSUIT trial dataPURSUIT trial data

Mortality in Non-ST Mortality in Non-ST ACS Patients With ACS Patients WithMyocardial Infarction During HospitalizationMyocardial Infarction During Hospitalization

Fintel D, ACC, 2000Fintel D, ACC, 2000

18.318.3%%

5.5%5.5%

12.8% 12.8%

(P(P = 0.0001)= 0.0001)

Patients with MI within Patients with MI within 72 hours (n=593)72 hours (n=593)

Patients without MI within Patients without MI within 72 hours (n=8,868)72 hours (n=8,868)

Days following randomizationDays following randomization

%

Mo

rtal

ity

%

Mo

rtal

ity

3030 6060 9090 120120 150150 180180

20202020

15151515

10101010

5555

Immediate ManagementImmediate ManagementImmediate ManagementImmediate Management

Classify as non-cardiac, chronic stable angina, Classify as non-cardiac, chronic stable angina, possible ACS, or definite ACSpossible ACS, or definite ACS

Evaluate for immediate reperfusion therapy if Evaluate for immediate reperfusion therapy if definite ACS and ST-segment definite ACS and ST-segment present present

Admit pts with definite ACS, ongoing pain, Admit pts with definite ACS, ongoing pain, biomarkers, new ST biomarkers, new ST or deep T-wave inversion, or deep T-wave inversion, abnormal hemodynamics, or (+) stress testabnormal hemodynamics, or (+) stress test

Pharmacological or exercise stress test, if possible Pharmacological or exercise stress test, if possible ACS and serial biomarkers and ECGs are normalACS and serial biomarkers and ECGs are normal

Classify as non-cardiac, chronic stable angina, Classify as non-cardiac, chronic stable angina, possible ACS, or definite ACSpossible ACS, or definite ACS

Evaluate for immediate reperfusion therapy if Evaluate for immediate reperfusion therapy if definite ACS and ST-segment definite ACS and ST-segment present present

Admit pts with definite ACS, ongoing pain, Admit pts with definite ACS, ongoing pain, biomarkers, new ST biomarkers, new ST or deep T-wave inversion, or deep T-wave inversion, abnormal hemodynamics, or (+) stress testabnormal hemodynamics, or (+) stress test

Pharmacological or exercise stress test, if possible Pharmacological or exercise stress test, if possible ACS and serial biomarkers and ECGs are normalACS and serial biomarkers and ECGs are normal

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

High likelihoodHigh likelihood•Typical anginaTypical angina•Known hx of CAD or MIKnown hx of CAD or MI•CHFCHF•New ECG changesNew ECG changesTroponin or CK-MBTroponin or CK-MB

Intermediate likelihoodIntermediate likelihood•Probable anginaProbable angina•Age > 70 yrsAge > 70 yrs•MaleMale•DiabetesDiabetes•PVD, CVAPVD, CVA•Old ECG abnormalitiesOld ECG abnormalities

Initial Chest PainInitial Chest PainEvaluationEvaluation

Symptoms Suggestive of ACSSymptoms Suggestive of ACS

Definite ACSDefinite ACS

Initial Chest PainInitial Chest PainEvaluationEvaluation

Symptoms Suggestive of ACSSymptoms Suggestive of ACS

Definite ACSDefinite ACSPossible ACSPossible ACS

(–) ECG;Normal biomarkers

(–) ECG;Normal biomarkers

Observe; repeat ECG, markers at 4-8 hrs

Observe; repeat ECG, markers at 4-8 hrs

No recurrent pain;(–) follow-up studiesNo recurrent pain;

(–) follow-up studiesRecurrent pain;

(+) follow-up studiesRecurrent pain;

(+) follow-up studies

Stress test; LVfunction

Stress test; LVfunction

(–) test: outpt follow-up(–) test: outpt follow-up

(+) test(+) test

Admit, treat for acute ischemiaAdmit, treat for acute ischemia

ST ST

Use MI Guidelines

Use MI Guidelines

No ST No ST

ST-T ’s,chest pain, markers

ST-T ’s,chest pain, markers

ACC/AHA “High-risk” for initiation of GP 2b3a inhibitor: • Age > 75• Prolonged, ongoing CP• Hemodynamic instability• Rest CP with ST • VT• Positive cardiac markers ACC/AHA “High-risk” for triage to early invasive management

strategy: • Recurrent ischemia, despite medsRecurrent ischemia, despite meds• Elevated Troponin I or TElevated Troponin I or T• New ST-segment depressionNew ST-segment depression• New CHF symptomsNew CHF symptoms• High-risk stress test findingsHigh-risk stress test findings• LV dysfunction (EF < 40%)LV dysfunction (EF < 40%)• Hemodynamic instability, sustained VT Hemodynamic instability, sustained VT • PCI within 6 months, prior CABGPCI within 6 months, prior CABG

ACC/AHA “High-risk” for initiation of GP 2b3a inhibitor: • Age > 75• Prolonged, ongoing CP• Hemodynamic instability• Rest CP with ST • VT• Positive cardiac markers ACC/AHA “High-risk” for triage to early invasive management

strategy: • Recurrent ischemia, despite medsRecurrent ischemia, despite meds• Elevated Troponin I or TElevated Troponin I or T• New ST-segment depressionNew ST-segment depression• New CHF symptomsNew CHF symptoms• High-risk stress test findingsHigh-risk stress test findings• LV dysfunction (EF < 40%)LV dysfunction (EF < 40%)• Hemodynamic instability, sustained VT Hemodynamic instability, sustained VT • PCI within 6 months, prior CABGPCI within 6 months, prior CABG

Risk Stratification Tools and Strategy in ACSRisk Stratification Tools and Strategy in ACS

Age is not a factorAge is not a factor

Risk Stratification Tools and Strategy in ACSRisk Stratification Tools and Strategy in ACS

FRISC IIFRISC IIAge>70Age>70

DiabetesDiabetesPrevious MIPrevious MI

Previous Severe AnginaPrevious Severe AnginaST - DepressionST - Depression

Troponin positiveTroponin positive

0-10-1 >> 22

InvasiveInvasive•ASA,ß-blockadeASA,ß-blockade•LMWHLMWH•IIb/IIIa blockadeIIb/IIIa blockade

Within Hrs-DaysWithin Hrs-Days•PCI/CABGPCI/CABG

NoninvasiveNoninvasive•ASA,ß-blockadeASA,ß-blockade•LMWHLMWH

If Severe IschemiaIf Severe Ischemia•IIb/IIIa blockadeIIb/IIIa blockade•PCI/CABGPCI/CABG

TIMITIMIAge≥65Age≥65

≥≥3 CAD risk factors3 CAD risk factorsKnown CADKnown CADPrior ASAPrior ASA

≥≥2 rest angina w/in 24º2 rest angina w/in 24ºTroponin positiveTroponin positiveST - DepressionST - Depression

≥≥330-20-2

Anti-ischemic Therapy for Anti-ischemic Therapy for ACSACS

• Bed RestBed Rest• OxygenOxygen• Nitrates (sublingual then oral/topical, IV Nitrates (sublingual then oral/topical, IV

for ongoing pain)for ongoing pain)• Morphine IV (for pain, CHF)Morphine IV (for pain, CHF)• ββ-blocker (IV if ongoing pain, then oral)-blocker (IV if ongoing pain, then oral)• Nondihydropyridine CaNondihydropyridine Ca2+ 2+ blocker blocker

(e.g.verapamil or diltiazem) if beta (e.g.verapamil or diltiazem) if beta blocker is contraindicatedblocker is contraindicated

• ACE Inhibitor for HTN, low EF, CHF, or ACE Inhibitor for HTN, low EF, CHF, or DMDM

Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

Plaque rupture

Platelet adhesion

Platelet activation

unstable angina & non-ST elevation MI

Microembolization

Totally occlusive arterial thrombosis & ST elevation MI

Pathogenesis of Acute Coronary SyndromesPathogenesis of Acute Coronary SyndromesPathogenesis of Acute Coronary SyndromesPathogenesis of Acute Coronary Syndromes

Platelet aggregation

+ troponin

Ischemic Complications of PCIIatrogenic ACS

Ischemic Complications of PCIIatrogenic ACS

White HD. AM J Cardiol. 1997; 80(4A): 2B-10B.

Intracoronary stenting

Percutaneous coronaryintervention

Plaque rupture/fissure

Thrombus formation

Microembolization

Treatment Goals for Acute Treatment Goals for Acute Medical Therapies for Non-ST-Medical Therapies for Non-ST-Elevation ACSElevation ACS

• Limit downstream embolizationLimit downstream embolization

• Reduce risk of early adverse eventsReduce risk of early adverse events• Death, (Re-) MI, recurrent ischemiaDeath, (Re-) MI, recurrent ischemia

• Improve safety and outcomes of Improve safety and outcomes of early revascularization proceduresearly revascularization procedures

Hospital CareHospital CareAnti-Thrombotic TherapyAnti-Thrombotic Therapy

Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

Aspirin + clopidogrel for up to 1 Aspirin + clopidogrel for up to 1 month, if medical therapy or PCI is month, if medical therapy or PCI is plannedplanned

Heparin (IV unfractionated, LMW) Heparin (IV unfractionated, LMW) with antiplatelet agents listed abovewith antiplatelet agents listed above

Enoxaparin preferred over UFH Enoxaparin preferred over UFH unless CABG is planned within 24 unless CABG is planned within 24 hourshours

Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

Aspirin + clopidogrel for up to 1 Aspirin + clopidogrel for up to 1 month, if medical therapy or PCI is month, if medical therapy or PCI is plannedplanned

Heparin (IV unfractionated, LMW) Heparin (IV unfractionated, LMW) with antiplatelet agents listed abovewith antiplatelet agents listed above

Enoxaparin preferred over UFH Enoxaparin preferred over UFH unless CABG is planned within 24 unless CABG is planned within 24 hourshours

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

00 1.01.0 2.02.0 Favors PlaceboFavors Aspirin

Cairns

Lewis

Theroux

Wallentin

Pooled

Cairns

Lewis

Theroux

Wallentin

Pooled

Relative Risk — Death or MIRelative Risk — Death or MI

Antithrombotic therapy in Non Antithrombotic therapy in Non STSTACSACSEvidence for AspirinEvidence for Aspirin

Relative Risk of Death or MIRelative Risk of Death or MIRelative Risk of Death or MIRelative Risk of Death or MI

Theroux (n = 243)

RISC (n = 399)

Cohen (n = 69)

Cohen (n = 214)

Holdright (n = 185)

Gurfinkel (n = 143)

Overall (n = 1353)

Theroux (n = 243)

RISC (n = 399)

Cohen (n = 69)

Cohen (n = 214)

Holdright (n = 185)

Gurfinkel (n = 143)

Overall (n = 1353)

0.50.5 11 1.51.5 22

ASA + UFH BetterASA + UFH Better ASA BetterASA Better

00

2.662.66

6.876.87

Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996

Antithrombotic therapy in Non Antithrombotic therapy in Non STSTACSACSEvidence for Heparin Use (UFH + ASA versus Evidence for Heparin Use (UFH + ASA versus ASA)ASA)

P = 0.06P = 0.06

Trial:Trial:

FRICFRIC(Dalteparin; n = 1,482)(Dalteparin; n = 1,482)

FRAXISFRAXIS(nadroparin; n = 2,357)(nadroparin; n = 2,357)

ESSENCEESSENCE(enoxaparin; n = 3,171)(enoxaparin; n = 3,171)

TIMI 11BTIMI 11B(enoxaparin; n = 3,910)(enoxaparin; n = 3,910)

Trial:Trial:

FRICFRIC(Dalteparin; n = 1,482)(Dalteparin; n = 1,482)

FRAXISFRAXIS(nadroparin; n = 2,357)(nadroparin; n = 2,357)

ESSENCEESSENCE(enoxaparin; n = 3,171)(enoxaparin; n = 3,171)

TIMI 11BTIMI 11B(enoxaparin; n = 3,910)(enoxaparin; n = 3,910)

.75.75 1.01.0 1.51.5.75.75 1.01.0 1.51.5

(p= 0.032)(p= 0.032)(p= 0.032)(p= 0.032)

(p= 0.029)(p= 0.029)(p= 0.029)(p= 0.029)

Braunwald E, Circulation 2000Braunwald E, Circulation 2000

LMWHBetterLMWHBetter

UFHBetterUFH

Better

LMWH vs. UFH in Non-ST LMWH vs. UFH in Non-ST ACS:ACS:Effect on Death, MI, Recurrent Effect on Death, MI, Recurrent IschemiaIschemia

Study Study GP 2b3a GP 2b3a InhibitorInhibitor

Time of Time of primary primary end point end point

Enox Enox (%) (%)

UFH (%) UFH (%)

ESSENCESSENCE E

NoNo 8 days 8 days 9.2 9.2 12.1 12.1

TIMI 11B TIMI 11B NoNo 8 days 8 days 12.4 12.4 14.5 14.5

INTERACINTERACT T

IntegrelinIntegrelin 7 days 7 days 6.3 6.3 9.6 9.6

A to Z A to Z AggrastatAggrastat 7 days 7 days 8.4 8.4 9.4 9.4

Major trials of Enoxaparin vs UFH Major trials of Enoxaparin vs UFH

in ACS in ACS Death/MI/refractory ischemiaDeath/MI/refractory ischemia

Blazing M. American College of Cardiology Annual Scientific Sessions. Mar 31-Apr 4, 2003; Chicago, IL.

Bleeding Bleeding resultsresults

Blazing M. American College of Cardiology Annual Scientific Sessions. Mar 31-Apr 4, 2003; Chicago, IL.

Result Result EnoxapariEnoxaparin (%) n (%)

Heparin Heparin (%) (%)

Combined TIMI Combined TIMI major/minor major/minor bleeding bleeding

3.1 3.1 2.2 2.2

TIMI major TIMI major bleeding bleeding

0.9 0.9 0.4 0.4

TIMI minor TIMI minor bleeding bleeding

2.2 2.2 1.8 1.8

Transfusions Transfusions 1 1 0.8 0.8

All results are nonsignificant

Hospital CareHospital CarePlatelet GP IIb/IIIa InhibitorsPlatelet GP IIb/IIIa Inhibitors

Any GP IIb/IIIa inhibitor + ASA/Heparin for all Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI plannedpatients, if cath/PCI planned

Eptifibatide or tirofiban + ASA/Heparin for high-Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not plannedrisk* patients in whom early cath/PCI is not planned

Any GP IIb/IIIa inhibitor for patients already on Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is plannedASA + Heparin + clopidogrel, if cath/PCI is planned

Any GP IIb/IIIa inhibitor + ASA/Heparin for all Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI plannedpatients, if cath/PCI planned

Eptifibatide or tirofiban + ASA/Heparin for high-Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not plannedrisk* patients in whom early cath/PCI is not planned

Any GP IIb/IIIa inhibitor for patients already on Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is plannedASA + Heparin + clopidogrel, if cath/PCI is planned

II IIaIIa IIbIIb IIIIII

* High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers * High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers

+24 h +48 h

N=1228N=1228PP=0.105=0.105

7.6%7.6%

10.3%10.3%

Eptifibatide Eptifibatide heparin heparin

HeparinHeparin

Boersma et al. Boersma et al. Circulation.Circulation. 1999;100:2045-2048. 1999;100:2045-2048.

N=1239P=0.009

+24 h +48 h

HeparinHeparin5.8%5.8%

2.8%2.8%AbciximabAbciximab

CAPTURECAPTURE

+24 h +48 h

8.0%8.0%HeparinHeparin

Tirofiban + heparinTirofiban + heparin2.9%2.9%

N=287N=287PP=0.062=0.062

PRISM-PLUSPRISM-PLUS

PURSUITPURSUIT

PCI

PCI

PCI

GP 2b/3a Inhibitors in ACS Trials:GP 2b/3a Inhibitors in ACS Trials:Death/MI in All Patients and Postprocedure in PCI GroupsDeath/MI in All Patients and Postprocedure in PCI Groups

%%

10

8

6

42

0

N=9461P=0.003

+24 h +48 h +72 hGP IIb/IIIa

4.4%4.4%

3.2%3.2%

N=1570P=0.016

10

8

6

4

2

0

%%

+24 h +48 h +72 hGP IIb/IIIa

1.8%1.8%

3.8%3.8%

N=1265P=0.032

+24 h

0

10

8

6

4

2

%%

GP IIb/IIIa

2.8%2.8%1.3%1.3%

GP IIb/IIIa Inhibitors in ACS Trials:GP IIb/IIIa Inhibitors in ACS Trials:Death/MI in All Patients and Postprocedure in PCI GroupsDeath/MI in All Patients and Postprocedure in PCI Groups

Early PCI

Eptifibatide

Eptifibatide

(PURSUIT)

(PURSUIT)

Tirofiban

Tirofiban

(PRISM Plus)

(PRISM Plus)

Abciximab

Abciximab

(CAPTURE)

(CAPTURE)

16.7

10.2

9

11.6

5.94.8

0

2

4

6

8

10

12

14

16

18

20

p=0.01

p=nsp=0.003

% I

nci

den

ce D

eath

/MI

at 3

0 d

ays

PlaceboPlaceboIIb/IIIa IIb/IIIa InhibitorInhibitor

15.6

10.1

8

14.5

7.88.7

0

2

4

6

8

10

12

14

16

18

p=ns

p=ns

p=ns

No Early PCI

% I

nci

den

ce D

eath

/MI

at 3

0 d

ays

Eptifibatide

Eptifibatide

(PURSUIT)

(PURSUIT)

Tirofiban

Tirofiban

(PRISM Plus)

(PRISM Plus)

Abciximab

Abciximab

(GUSTO IV)

(GUSTO IV)

PlaceboPlaceboIIb/IIIaIIb/IIIa InhibitorInhibitor

15

10

5

0

0 5 10 15 20 25 30Follow-up (days)Follow-up (days)

Dea

th o

r M

I (%

)D

eath

or

MI

(%)

TnI + with heparinTnI + with tirofiban

Heeschen et al. Heeschen et al. LancetLancet. 1999;354:1757-1762.. 1999;354:1757-1762.

PRISM Trial: PRISM Trial: Troponin-I Positive Troponin-I Positive Patients Benefit Patients Benefit From GP From GP IIb/IIIa AdditionIIb/IIIa Addition

TnI - with heparinTnI - with tirofiban

Hospital CareHospital CareConservative vs. Invasive Conservative vs. Invasive StrategiesStrategies

Early invasive strategy in high-risk Early invasive strategy in high-risk patients with any of the following:patients with any of the following:

- Recurrent ischemia, despite meds- Recurrent ischemia, despite meds- Elevated Troponin I or T- Elevated Troponin I or T- New ST-segment depression- New ST-segment depression- New CHF symptoms- New CHF symptoms- High-risk stress test findings- High-risk stress test findings- LV dysfunction (EF < 40%)- LV dysfunction (EF < 40%)- Hemodynamic instability, sustained VT- Hemodynamic instability, sustained VT- PCI within 6 months, prior CABG- PCI within 6 months, prior CABG

Early invasive strategy in high-risk Early invasive strategy in high-risk patients with any of the following:patients with any of the following:

- Recurrent ischemia, despite meds- Recurrent ischemia, despite meds- Elevated Troponin I or T- Elevated Troponin I or T- New ST-segment depression- New ST-segment depression- New CHF symptoms- New CHF symptoms- High-risk stress test findings- High-risk stress test findings- LV dysfunction (EF < 40%)- LV dysfunction (EF < 40%)- Hemodynamic instability, sustained VT- Hemodynamic instability, sustained VT- PCI within 6 months, prior CABG- PCI within 6 months, prior CABG

II IIaIIa IIbIIb IIIIII

FRISC IIFRISC II

0 30 60 90 120 150 1800

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Invasive Strategy

Non-invasive Strategy

p=0.031

DaysDays

Pro

babi

lity

of

Dea

th o

r M

IP

roba

bili

ty o

f D

eath

or

MI

Invasive vs Noninvasive Strategy in ACSInvasive vs Noninvasive Strategy in ACSn=2457n=2457

Lancet 1999;354:708-715Lancet 1999;354:708-715

22% Risk Reduction22% Risk Reduction

FRISC II - 12 month MortalityFRISC II - 12 month Mortality

Noninvasive (n=1235)

Invasive (n=1222)

Invasive Noninvasive RR (95%CI) p 2.2% 3.9% 0.57 (0.36-0.90) 0.016

0

.01

.02

.03

.04

0 90 180 270 360

DaysDays

Pro

babi

lity

of D

eath

Pro

babi

lity

of D

eath

FRISC II - FRISC II - Troponin T/ST depression and Troponin T/ST depression and OutcomeOutcome

0 60 120 180 240 300 3600

4

8

12

16

20

0 60 120 180 240 300 360

4

8

12

16

20

0

ST depST depnon-invasivenon-invasive

ST depST depinvasiveinvasive

No ST depNo ST depnon-invasivenon-invasive

No ST depNo ST depinvasiveinvasive

% Death or MI% Death or MI

Positive Troponin T (≥0.03 Positive Troponin T (≥0.03 g/L)g/L)non-invasivenon-invasive

Positive Troponin T (≥0.03 Positive Troponin T (≥0.03 g/L)g/L)invasiveinvasive

Negative Troponin TNegative Troponin Tnon-invasivenon-invasive

Negative Troponin TNegative Troponin Tinvasiveinvasive

p=0.007p=0.007 p=0.01p=0.01

Lancet 1999;354:708-715Lancet 1999;354:708-715

0 1 2 3 4 5 6Time (months)

0

4

8

12

16

20

% P

ati

ents

CONS

INV

O.R 0.7895% CI (0.62, 0.97)

p=0.025

19.4%

15.9%

TACTICS-TIMI-18: Primary TACTICS-TIMI-18: Primary Endpoint: Endpoint: Death, MI, Rehospitalization for ACS at 6 Death, MI, Rehospitalization for ACS at 6

MonthsMonths

TACTICS-TIMI-18: Primary TACTICS-TIMI-18: Primary Endpoint: Endpoint: Death, MI, Rehospitalization for ACS at 6 Death, MI, Rehospitalization for ACS at 6

MonthsMonths

Cannon C, AHA 2000Cannon C, AHA 2000Cannon C, AHA 2000Cannon C, AHA 2000

14.5

24.226.3

16.914.3 15.6 16.415.3

0

5

10

15

20

25

30

TnT - TnT + No STshift

ST shift

CONS INV

TACTICS - Troponin T/ST segment shift

TnT cut point = 0.01 ng/ml

% Composite EP (Death, MI, Rehosp) at 6 Months% Composite EP (Death, MI, Rehosp) at 6 Months

NEJM 2001;345:494-502NEJM 2001;345:494-502

Benefit of IIb/IIIa InhibitorBenefit of IIb/IIIa InhibitorProbability of MIProbability of MI

FRISC IIFRISC II TACTICSTACTICS

0

.02

.04

.06

.08

.10

.12

.14

0 30 60 90 120 150 180

0

.02

.04

.06

.08

.10

.12

.14

0 30 60 90 120 150 180

CONS

INV

CONS

INV

Day 7Day 7OR=0.59OR=0.59P=0.033P=0.033

Day 30Day 30OR=0.51OR=0.51P=0.002P=0.002

DaysDays

Hospital CareHospital CareConservative vs. Invasive Conservative vs. Invasive Strategies (2)Strategies (2)

Either strategy in low- to Either strategy in low- to moderate-risk patients without moderate-risk patients without contraindications to contraindications to revascularizationrevascularization

Early invasive strategy for patients Early invasive strategy for patients with repeated ACS presentations, with repeated ACS presentations, without high-risk features or without high-risk features or ongoing ischemiaongoing ischemia

Either strategy in low- to Either strategy in low- to moderate-risk patients without moderate-risk patients without contraindications to contraindications to revascularizationrevascularization

Early invasive strategy for patients Early invasive strategy for patients with repeated ACS presentations, with repeated ACS presentations, without high-risk features or without high-risk features or ongoing ischemiaongoing ischemia

II IIaIIa IIbIIb IIIIII

Hospital CareHospital CareClopidogrel TherapyClopidogrel Therapy

Aspirin + clopidogrel, for up to 1 Aspirin + clopidogrel, for up to 1 month*month*

Aspirin + clopidogrel, for up to 9 Aspirin + clopidogrel, for up to 9 months*months*

Withhold clopidogrel for 5-7 days for Withhold clopidogrel for 5-7 days for CABGCABG

Aspirin + clopidogrel, for up to 1 Aspirin + clopidogrel, for up to 1 month*month*

Aspirin + clopidogrel, for up to 9 Aspirin + clopidogrel, for up to 9 months*months*

Withhold clopidogrel for 5-7 days for Withhold clopidogrel for 5-7 days for CABGCABG

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

* For patients managed with an early conservative strategy, and * For patients managed with an early conservative strategy, and those who are planned to undergo early PCIthose who are planned to undergo early PCI* For patients managed with an early conservative strategy, and * For patients managed with an early conservative strategy, and those who are planned to undergo early PCIthose who are planned to undergo early PCI

Guidelines do not specify initial approach to using Guidelines do not specify initial approach to using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknownGuidelines do not specify initial approach to using Guidelines do not specify initial approach to using clopidogrel when coronary anatomy is unknownclopidogrel when coronary anatomy is unknown

00

22

44

66

88

1010

1212

1414

Dea

th, M

I, o

r S

tro

keD

eath

, MI,

or

Str

oke

Clopidogrel Clopidogrel + ASA+ ASA

33 66 99

Placebo Placebo + ASA+ ASA

Months of Follow-UpMonths of Follow-Up

11.4%11.4%

9.3%9.3%

20% RRR20% RRRPP < 0.001 < 0.001

N = 12,562N = 12,562

00 1212

N Engl J Med. 2001N Engl J Med. 2001

CURE Primary ResultsCURE Primary Results

%%%%

CURE Trial: Main Efficacy ResultsCURE Trial: Main Efficacy Results

11.5

9.3

5.4 5.1

6.7

5.2

1.4 1.2 0.7 0.7

0

2.5

5

7.5

10

12.5

15

PlaceboClopidogrel

p<.00005

p<.001ns

nsns

Composite:Composite:CV Death,CV Death,MI,StrokeMI,Stroke

(1(1oo Endpoint) Endpoint)

CV DeathCV Death MIMI StrokeStroke Non CVNon CVDeathDeath

19% reduction19% reduction

NEJM 2001;345:494-502NEJM 2001;345:494-502

CURE: Effects of CURE: Effects of Clopidogrel stratified by Clopidogrel stratified by TIMI Risk ScoreTIMI Risk ScoreOutcome at 12 monthsOutcome at 12 months

5.74.1

11.49.8

20.7

15.9

0

5

10

15

20

25

TIMI Score 0-2Low-risk (n=3276)

TIMI Score 3-4Moderate-risk

(n=7297)

TIMI Score 5-7High-risk (n=1989)

PlaceboClopidogrel

CV

Dea

th/M

I/S

trok

e (%

)C

V D

eath

/MI/

Str

oke

(%)

p=0.03p=0.03

p=0.02p=0.02

p=0.003p=0.003

PCI

PLACEBO + ASA *

CLOPIDOGREL+ ASA *

30 days post PCI

End of follow-upUp to 12 months

after randomization

Open-label thienopyridineOpen-label thienopyridine

Pretreatment

Open-label thienopyridineOpen-label thienopyridine

PretreatmentN = 2,658 patients undergoing PCI

* In combination with standard therapy

N = 1345

N = 1313

CURE PCI-CURE

PCI-CURE SubstudyPCI-CURE Substudy

R

Mehta, SR. et al for the CURE Trial Investigators CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

0.150.15

0.100.10

0.050.05

0.00.0

0 100100 200200 300300 400400Days of follow-upDays of follow-up

12.6%12.6%

8.8%8.8%

31% RRR31% RRRP P = 0.002= 0.002N = 2658N = 2658

ClopidogrelClopidogrel+ ASA*+ ASA*

PlaceboPlacebo+ ASA*+ ASA*

Cu

mu

lati

ve H

azar

d R

ate

* In combination with standard therapy

Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001.

Composite of cardiovascular death or MI from randomization to end of follow-upComposite of cardiovascular death or MI from randomization to end of follow-up

PCI-CURE: Overall Long-Term PCI-CURE: Overall Long-Term ResultsResults

RRR P value

Placebo + ASA*

N = 1345

Clopidogrel + ASA*

N = 1313

•From PCI to 30 daysFrom PCI to 30 days

MI, urgent revascularizationMI, urgent revascularizationor CV death or CV death 6.4%6.4% 4.5%4.5% 30%30% 0.030.03

•From PCI to follow-upFrom PCI to follow-up

CV death or MI CV death or MI 8.0%8.0% 6.0%6.0% 25%25%0.0470.047

PCI-CURE: Efficacy PCI-CURE: Efficacy OutcomesOutcomes

* In combination with standard therapy* In combination with standard therapy

Mehta, SR. et al for the CURE Trial Investigators. Lancet. August 2001;21:2033-41.

Bleeding RiskBleeding Risk

p valuep valueRelative Relative riskrisk

Aspirin Aspirin (n=6303)(n=6303)

EndpointEndpoint

Major bleedingMajor bleeding

Aspirin + clopidogrel

(n=6259)

2.7%2.7% 3.6%3.6% 1.341.34

N/AN/A2.1%2.1%Life-threatening Life-threatening bleedingbleeding

1.8%1.8% 1.151.15

0.0030.003

8.6%8.6%Minor bleedingMinor bleeding

TransfusionsTransfusions 2.8%2.8%

<0.001<0.001

2.2%2.2%

15.3%15.3% 1.781.78

1.281.28 0.030.03

NEJM 2001;345:494-502NEJM 2001;345:494-502

Discharge/Post-Discharge Discharge/Post-Discharge MedicationsMedications

ASA, if not contraindicatedASA, if not contraindicated

Clopidogrel, when ASA contraindicatedClopidogrel, when ASA contraindicated

Aspirin + Clopidogrel, for up to 9 monthsAspirin + Clopidogrel, for up to 9 months

-blocker, if not contraindicated-blocker, if not contraindicated

Lipid Lipid agents + diet, if LDL >130 mg/dL agents + diet, if LDL >130 mg/dL

ACE Inhibitor: CHF, EF < 40%, DM, or HTNACE Inhibitor: CHF, EF < 40%, DM, or HTN

ASA, if not contraindicatedASA, if not contraindicated

Clopidogrel, when ASA contraindicatedClopidogrel, when ASA contraindicated

Aspirin + Clopidogrel, for up to 9 monthsAspirin + Clopidogrel, for up to 9 months

-blocker, if not contraindicated-blocker, if not contraindicated

Lipid Lipid agents + diet, if LDL >130 mg/dL agents + diet, if LDL >130 mg/dL

ACE Inhibitor: CHF, EF < 40%, DM, or HTNACE Inhibitor: CHF, EF < 40%, DM, or HTN

II IIaIIa IIbIIb IIIIII

95%86%

92%

47%

85%

64%71%

20%

0%

20%

40%

60%

80%

100%

ASA <24 BB <24 Heparin GP IIb/IIIa

Leading Centers Lagging Centers

CRUSADE Registry: Leading and CRUSADE Registry: Leading and Lagging Hospital QuartilesLagging Hospital Quartiles Acute CareAcute Care

CRUSADE Registry: Leading and CRUSADE Registry: Leading and Lagging Hospital QuartilesLagging Hospital Quartiles Acute CareAcute Care

CRUSADE Registry: Gap between CRUSADE Registry: Gap between Leading and Lagging Hospitals Leading and Lagging Hospitals Quartiles: Quartiles: Discharge CareDischarge Care

94% 89%

67%78%

60%

82%

68%

49%58%

36%

0%

20%

40%

60%

80%

100%

D/C ASA D/C BB D/C ACE* Statin# Clopidogrel

Leading Centers Lagging Centers* LVEF < 40%* LVEF < 40%# Known hyperlipidemia# Known hyperlipidemia* LVEF < 40%* LVEF < 40%# Known hyperlipidemia# Known hyperlipidemia

0

1

2

3

4

5

6

7

<65% 65-75% 75-80% >80%

Hospital Composite Adherence Quartiles

In-h

osp

ital

Mo

rtal

ity

(%)

Performance Matters!Performance Matters!Relationship between Process and Relationship between Process and OutcomeOutcome

5.95.9

5.05.04.64.6

3.63.6

Questions?Questions?