6/046/04

ACC/AHA Guidelines for the ACC/AHA Guidelines for the Management of Patients with Management of Patients with Unstable Angina and Non-ST-Unstable Angina and Non-ST-

Segment Elevation MISegment Elevation MI

Published in JACC and CirculationPublished in JACC and CirculationSeptember, 2000September, 2000

Revisions Released in March, 2002Revisions Released in March, 2002

Guidelines Issues for Emergency Medicine:Guidelines Issues for Emergency Medicine:Pollack CV, Gibler WB. Ann Emerg Med 2001Pollack CV, Gibler WB. Ann Emerg Med 2001Guidelines Issues for Emergency Medicine:Guidelines Issues for Emergency Medicine:

Pollack CV, Gibler WB. Ann Emerg Med 2001Pollack CV, Gibler WB. Ann Emerg Med 2001

6/046/04

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. 1997

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

6/046/04WHO – 2000, NCHS 2000AHA - 2000 Heart and Stroke Statistical Update

Ischemic Heart DiseaseIschemic Heart DiseaseUnstable Angina and Acute MIUnstable Angina and Acute MI

12,200,000 people in the US have had an MI, 12,200,000 people in the US have had an MI, angina pectoris, or bothangina pectoris, or both

5,315,000 Americans visited Emergency 5,315,000 Americans visited Emergency Departments for chest pain in 1997Departments for chest pain in 1997

1,433,000 Americans hospitalized for IHD in 19961,433,000 Americans hospitalized for IHD in 1996 225,000 died before hospital225,000 died before hospital

1,100,000 Americans will have a new or repeat 1,100,000 Americans will have a new or repeat IHD event this yearIHD event this year

6/046/04

EmergencyEmergencyDepartmentDepartment

In-HospitalIn-Hospital

PresentationPresentation

++++

Ischemic Discomfort Ischemic Discomfort at Restat Rest

No ST-Segment No ST-Segment ElevationElevation

Non-Q-wave MIUnstable Angina

Q-wave MI

ST-Segment Elevation

++ ++

( : positive cardiac biomarker)

Spectrum of Acute Coronary SyndromesSpectrum of Acute Coronary Syndromes

6/046/04

Participants in Updated Guidelines Participants in Updated Guidelines

6/046/04

Co

mm

itte

eC

om

mit

tee

Updated GuidelinesUpdated GuidelinesReview ProcessReview Process

ReviewersReviewers 3 AHA3 AHA 1 ACP-ASIM1 ACP-ASIM 3 ACC3 ACC 1 ESC1 ESC 3 ACEP3 ACEP 1 STS1 STS 1 AAFP1 AAFP 29 Others29 Others

ReviewersReviewers 3 AHA3 AHA 1 ACP-ASIM1 ACP-ASIM 3 ACC3 ACC 1 ESC1 ESC 3 ACEP3 ACEP 1 STS1 STS 1 AAFP1 AAFP 29 Others29 Others

Original Original GuidelinesGuidelinesOriginal Original GuidelinesGuidelines

Literature searchesLiterature searchesLiterature searchesLiterature searches

Evidence tablesEvidence tablesEvidence tablesEvidence tables

Revise Revise GuidelinesGuidelines draft draftRevise Revise GuidelinesGuidelines draft draft

Final Approval by ACC and AHAFinal Approval by ACC and AHAFinal Approval by ACC and AHAFinal Approval by ACC and AHA

6/046/04

Updated GuidelinesUpdated GuidelinesWeighing the EvidenceWeighing the Evidence

1994 version was starting point; literature searches 1994 version was starting point; literature searches

added more current reportsadded more current reports

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, Data from fewer, smaller randomized trials,

careful analyses of nonrandomized studies, careful analyses of nonrandomized studies,

observational registriesobservational registries

== Expert consensusExpert consensus

6/046/04

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

6/046/04

Prognosis in Unstable Angina / NSTEMIPrognosis in Unstable Angina / NSTEMI

PURSUIT trial dataPURSUIT trial data

6/046/04

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

6/046/04

Initial Chest Pain EvaluationInitial Chest Pain Evaluation

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 if ischemia

Stress test; LVfunction if ischemia

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

(+) test(+) test

Admit, Use AcuteIschemia PathwayAdmit, Use AcuteIschemia Pathway

ST ST

Use MI Guidelines

Use MI Guidelines

No ST No ST

ST-T ’s,chest pain, markers

ST-T ’s,chest pain, markers

Symptoms Suggestive of ACSSymptoms Suggestive of ACS

6/046/04

Hospital CareHospital CareAnti-Thrombotic TherapyAnti-Thrombotic Therapy

Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

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

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

Enoxaparin preferred over UFH unless Enoxaparin preferred over UFH unless CABG is planned within 24 hoursCABG is planned within 24 hours

Immediate aspirinImmediate aspirin

Clopidogrel, if aspirin contraindicatedClopidogrel, if aspirin contraindicated

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

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

Enoxaparin preferred over UFH unless Enoxaparin preferred over UFH unless CABG is planned within 24 hoursCABG is planned within 24 hours

IIII IIaIIaIIaIIa IIbIIbIIbIIb IIIIIIIIIIII

6/046/04

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

Acute Coronary Syndromes Without ST Acute Coronary Syndromes Without ST Evidence for AspirinEvidence for Aspirin

6/046/04Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996Oler A, JAMA 1996

Acute Coronary Syndromes without ST Acute Coronary Syndromes without ST Evidence for Heparin Use (UFH + ASA versus ASA)Evidence for Heparin Use (UFH + ASA versus ASA)

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 22ASA + UFH BetterASA + UFH Better ASA BetterASA Better

00

2.662.66

6.876.87

P = 0.06P = 0.06

6/046/04Braunwald E, Circulation 2000Braunwald E, Circulation 2000

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)

LMWHBetterLMWHBetter

UFHBetterUFH

Better

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

6/046/04

Hospital CareHospital CareClopidogrel TherapyClopidogrel Therapy

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

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

Withhold clopidogrel for 5-7 days for CABGWithhold clopidogrel for 5-7 days for CABG

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

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

Withhold clopidogrel for 5-7 days for CABGWithhold clopidogrel for 5-7 days for CABG

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

6/046/04

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 1212N Engl J Med. 2001N Engl J Med. 2001

CURE Primary ResultsCURE Primary Results

%%%%

6/046/04

Placebo Placebo + ASA+ ASA

((N = 6303)N = 6303)

Clopidogrel Clopidogrel + ASA+ ASA

(N = 6259)(N = 6259)

Major bleedingMajor bleeding 2.7% 3.7% 2.7% 3.7% 0.001 0.001

Life-threatening bleedingLife-threatening bleeding 1.8% 2.2% 1.8% 2.2% NS NS

Non-life-threatening bleedingNon-life-threatening bleeding 0.9% 1.5% 0.9% 1.5% 0.002 0.002

Minor bleedingMinor bleeding 2.4% 5.1% 2.4% 5.1% < 0.001 < 0.001

CURE – Bleeding ComplicationsCURE – Bleeding Complications

N Engl J Med, 2001N Engl J Med, 2001

P-ValueP-Value

6/046/04

1515

1010

55

00

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

Dea

th o

r N

on

fata

l M

ID

eath

or

No

nfa

tal

MI

Mehta S, Lancet Mehta S, Lancet 20012001

CURE PCI Sub-StudyCURE PCI Sub-StudyUpstream Clopidogrel Before PCI *Upstream Clopidogrel Before PCI *

%%%%

* Median Time to PCI = 6 Days* Median Time to PCI = 6 Days* Median Time to PCI = 6 Days* Median Time to PCI = 6 Days

6/046/04

Hospital CareHospital CareAnti-Ischemic Therapy (1)Anti-Ischemic Therapy (1)

-blocker (IV-blocker (IVoral) if not contraindicatedoral) if not contraindicated

Non-dihydropyridine CaNon-dihydropyridine Ca2+2+ antagonist if antagonist if --blocker contraindicated and no LV blocker contraindicated and no LV dysfunction, for recurrent ischemiadysfunction, for recurrent ischemia

ACE inhibitor if ACE inhibitor if BP persists with NTG+ BP persists with NTG+ -blocker, for pts with CHF or diabetes-blocker, for pts with CHF or diabetes

-blocker (IV-blocker (IVoral) if not contraindicatedoral) if not contraindicated

Non-dihydropyridine CaNon-dihydropyridine Ca2+2+ antagonist if antagonist if --blocker contraindicated and no LV blocker contraindicated and no LV dysfunction, for recurrent ischemiadysfunction, for recurrent ischemia

ACE inhibitor if ACE inhibitor if BP persists with NTG+ BP persists with NTG+ -blocker, for pts with CHF or diabetes-blocker, for pts with CHF or diabetes

II IIaIIa IIbIIb IIIIII

6/046/04

Hospital CareHospital CareAnti-Ischemic Therapy (2)Anti-Ischemic Therapy (2)

ACE inhibitor for all ACS ptsACE inhibitor for all ACS pts

Extended-release CaExtended-release Ca2+2+ blocker instead blocker instead of of -blocker -blocker

Immediate-release CaImmediate-release Ca2+2+ blocker with blocker with --blocker blocker

Long-acting CaLong-acting Ca2+2+ blocker for recurrent blocker for recurrent ischemia, if no contraindications and ischemia, if no contraindications and NTG + NTG + -blocker used fully-blocker used fully

ACE inhibitor for all ACS ptsACE inhibitor for all ACS pts

Extended-release CaExtended-release Ca2+2+ blocker instead blocker instead of of -blocker -blocker

Immediate-release CaImmediate-release Ca2+2+ blocker with blocker with --blocker blocker

Long-acting CaLong-acting Ca2+2+ blocker for recurrent blocker for recurrent ischemia, if no contraindications and ischemia, if no contraindications and NTG + NTG + -blocker used fully-blocker used fully

II IIaIIa IIbIIb IIIIII

6/046/04

Hospital CareHospital CarePlatelet GP IIb/IIIa Inhibitors (1)Platelet GP IIb/IIIa Inhibitors (1)

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

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

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

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

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

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

6/046/04

15.715.7

5.65.6

17.917.9

11.711.712.812.8

14.214.2

3.83.8

12.912.9

10.310.311.811.8

00

55

1010

1515

2020

Pri

mar

y E

nd

po

int

%P

rim

ary

En

dp

oin

t %

PlaceboPlacebo

GP IIb/IIIaGP IIb/IIIa

PURSUIT30 days

PURSUIT30 days

PRISM48 hrsPRISM48 hrs

PRISM PLUS7 days

PRISM PLUS7 days

P = 0.04P = 0.04P = 0.04P = 0.04 P = 0.01P = 0.01P = 0.01P = 0.01 P = 0.004P = 0.004P = 0.004P = 0.004

PARAGON A30 days

PARAGON A30 days

P = 0.48P = 0.48P = 0.48P = 0.48

PARAGON B30 days

PARAGON B30 days

P = 0.33P = 0.33

Platelet GP IIb/IIIa Inhibition for Non-ST Platelet GP IIb/IIIa Inhibition for Non-ST ACS ACSPrimary Endpoint Results from the 5 Major RCTsPrimary Endpoint Results from the 5 Major RCTs

6/046/04

Platelet GP IIb/IIIa Inhibition for Non ST Platelet GP IIb/IIIa Inhibition for Non ST ACS: ACS:Enhanced Benefit in Patients Undergoing Early PCIEnhanced Benefit in Patients Undergoing Early PCI

Platelet GP IIb/IIIa Inhibition for Non ST Platelet GP IIb/IIIa Inhibition for Non ST ACS: ACS:Enhanced Benefit in Patients Undergoing Early PCIEnhanced Benefit in Patients Undergoing Early PCI

10.2

16.718.5

5.9

11.6 11.6

0

10

20

PRISM-PLUS PURSUIT PARAGON-B

% 3

0-D

ay

De

ath

or

MI

Placebo GP IIb/IIIa

6/046/04

GP IIb/IIIa Blockade Before and After PCI: GP IIb/IIIa Blockade Before and After PCI: CAPTURE, PURSUIT, PRISM-PLUSCAPTURE, PURSUIT, PRISM-PLUS

Boersma, Circulation, 1999Boersma, Circulation, 1999

Dea

th o

r M

ID

eath

or

MI

0%

2%

4%

6%

8%

10%

PCIPCI

N=2754N=2754 P=0.001 P=0.001

N=12,296N=12,296P=0.001P=0.001

+24 h +48 h +72 h +24 h +48 h

4.3%4.3%

2.9%2.9%

8.0%8.0%

4.9%4.9%

Before PCIBefore PCI Post-PCIPost-PCI

PlaceboPlacebo

GP IIb/IIIa inhibitorGP IIb/IIIa inhibitor

0

6/046/04

00

1010

2020

3030

4040

00 3030 6060 9090 120120 150150 180180

Dea

th o

r M

I (%

)D

eath

or

MI

(%)

Days After RandomizationDays After Randomization

EptifibatideEptifibatide

PlaceboPlacebo

27.6%27.6%

32.7%32.7%

p = 0.02p = 0.02

Marso, Circulation 2000Marso, Circulation 2000Marso, Circulation 2000Marso, Circulation 2000

Platelet GP IIb/IIIa Blockade for Non-ST Platelet GP IIb/IIIa Blockade for Non-ST ACS: ACS: Pre-Treatment Before CABG in PURSUITPre-Treatment Before CABG in PURSUIT

Platelet GP IIb/IIIa Blockade for Non-ST Platelet GP IIb/IIIa Blockade for Non-ST ACS: ACS: Pre-Treatment Before CABG in PURSUITPre-Treatment Before CABG in PURSUIT

6/046/04

Hospital CareHospital CarePlatelet GP IIb/IIIa Inhibitors (2)Platelet GP IIb/IIIa Inhibitors (2)

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for patients without continuing for patients without continuing ischemia in whom PCI is not planned ischemia in whom PCI is not planned

Abciximab for patients in whom PCI is Abciximab for patients in whom PCI is not plannednot planned

Eptifibatide or tirofiban + ASA/Heparin Eptifibatide or tirofiban + ASA/Heparin for patients without continuing for patients without continuing ischemia in whom PCI is not planned ischemia in whom PCI is not planned

Abciximab for patients in whom PCI is Abciximab for patients in whom PCI is not plannednot planned

II IIaIIa IIbIIb IIIIII

6/046/04

Prolonged Infusions of Abciximab for Prolonged Infusions of Abciximab for Non-ST Non-ST ACS ACS

Medically refractory Medically refractory unstable anginaunstable angina

Culprit lesion identified Culprit lesion identified during angiographyduring angiography

Mandatory treatment Mandatory treatment period (18-24h) pre- PCIperiod (18-24h) pre- PCI

Infusion stopped 1 hr after Infusion stopped 1 hr after PCI completedPCI completed

Short duration of chest Short duration of chest pain (pain ( 10 mins) 10 mins)

ST ST ( ( 0.5 mm) or 0.5 mm) or elevated TnI / TnTelevated TnI / TnT

No angiography No angiography expected for 48 hrsexpected for 48 hrs

Medical management Medical management anticipatedanticipated

CAPTURECAPTURE GUSTO-IV ACS GUSTO-IV ACS CAPTURECAPTURE GUSTO-IV ACS GUSTO-IV ACS

6/046/04

CAPTURE ResultsCAPTURE ResultsCAPTURE ResultsCAPTURE Results

0

2

4

6

8

10

12 24 360

2

4

6

8

10

12 24 36 0 12 24 360 12 24 36

PTCAPTCA

p = 0.029p = 0.029 p = 0.009p = 0.009

placeboplaceboplacebo

abciximababciximababciximab

%%

Cath HoursHoursHoursHours

6/046/04

GUSTO-IV ACS Study DesignGUSTO-IV ACS Study Design

7800 Patients with Non-ST-Elevation ACS7800 Patients with Non-ST-Elevation ACS(( 0.5 mm ST 0.5 mm ST , + Troponin T or I), + Troponin T or I)

AbciximabAbciximabx 24 hrsx 24 hrs(n = 2590)(n = 2590)

AbciximabAbciximabx 48 hrsx 48 hrs(n = 2612)(n = 2612)

PlaceboPlacebo

(n = 2598)(n = 2598)

Aspirin + Unfractionated Heparin/DalteparinAspirin + Unfractionated Heparin/Dalteparin

No cath expected for 48 hoursNo cath expected for 48 hours

6/046/04

PlaceboPlacebo Abciximab24 hour

Abciximab24 hour

Abciximab48 hour

Abciximab48 hour

00

22

44

66

88

1010

1212

3.93.93.43.4

4.24.2

Death

Death or MI

%%

n = 2598n = 2598 n = 2590n = 2590 n = 2612n = 2612

8.08.0 8.28.29.19.1

GUSTO-IV ACS Primary EndpointGUSTO-IV ACS Primary Endpoint

Death or MI at 30 DaysDeath or MI at 30 Days

6/046/04

GP IIb/IIIa Inhibition for Non-ST-Elevation ACSGP IIb/IIIa Inhibition for Non-ST-Elevation ACS

30-Day Death or Nonfatal MI30-Day Death or Nonfatal MI

Risk Ratio & 95% CIRisk Ratio & 95% CI

Placebo Placebo BetterBetter

GP IIb/IIIa GP IIb/IIIa BetterBetter

TrialTrial

PooledPooled 11.5%11.5%

PlaceboPlaceboGP IIb/IIIaGP IIb/IIIa

10.7%10.7%29,85529,855

nn

0.92 (0.86, 0.92 (0.86, 0.995)0.995)

p = 0.037p = 0.037

PRISM PLUSPRISM PLUS 11.9%11.9% 10.2%10.2%1,9151,915

PURSUITPURSUIT 15.7%15.7% 14.2%14.2%9,4619,461

PARAGON APARAGON A 11.7%11.7% 11.3%11.3%2,2822,282

7.1%7.1%PRISMPRISM 5.8%5.8%3,2323,232

0.50.5 1.01.0 1.51.5

PARAGON BPARAGON B 11.4%11.4% 10.5%10.5%5,1655,165

GUSTO-IV GUSTO-IV ACSACS

8.0%8.0% 8.7%8.7%7,8007,800

Boersma, Lancet 2002Boersma, Lancet 2002Boersma, Lancet 2002Boersma, Lancet 2002

6/046/04

Hospital CareHospital CareConservative vs. Invasive Strategies (1)Conservative vs. Invasive Strategies (1)

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

6/046/04

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

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

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

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

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

II IIaIIa IIbIIb IIIIII

6/046/04

FRISC-II Mortality at One-Year FRISC-II Mortality at One-Year Invasive Vs. Conservative Management StrategiesInvasive Vs. Conservative Management Strategies

FRISC-II Mortality at One-Year FRISC-II Mortality at One-Year Invasive Vs. Conservative Management StrategiesInvasive Vs. Conservative Management Strategies

36018090300

Pro

bab

ility

of

Pro

bab

ility

of

DDe

ath

eat

h

.04

.03

.02

.01

0

Non-Invasive (n = 1235)Non-Invasive (n = 1235)

Invasive (n = 1222)Invasive (n = 1222)

InvasiveInvasive Noninvasive Noninvasive RR (95 % CI) RR (95 % CI) 2.2 %2.2 % 4.0 %4.0 % 0.56 (0.35 - 0.89) p = 0.018 0.56 (0.35 - 0.89) p = 0.018

Wallentin, Lancet 2000Wallentin, Lancet 2000Wallentin, Lancet 2000Wallentin, Lancet 2000

6/046/04

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

Death, MI, Rehospitalization for ACS at 6 MonthsDeath, MI, Rehospitalization for ACS at 6 Months

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

6/046/04FRISC-II Investigators, Lancet, 1999FRISC-II Investigators, Lancet, 1999

Early Invasive Management and Early Invasive Management and Enhanced Anti-Platelet TherapyEnhanced Anti-Platelet Therapy

FRISC II TACTICS-TIMI 18FRISC II TACTICS-TIMI 18

Low Molecular Weight Heparin GP IIb/IIIa InhibitorLow Molecular Weight Heparin GP IIb/IIIa Inhibitor

0 30 60 90 120 150 180

Time (days)

0.00

0.02

0.04

0.06

0.08

0.10

0.12

0.14

Pro

bab

ilit

y o

f M

IINV

CONS

CONSCONS

INVINV

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

6/046/04

Discharge/Post-Discharge MedicationsDischarge/Post-Discharge Medications

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

6/046/04

0%

5%

15%

0 1 2 3 4 5 6 7

Years Since RandomizationYears Since Randomization

Cu

mu

lati

ve M

ort

alit

y

Pravastatin

Placebo

• P = 0.00002• 23% reduction• 31 deaths avoided per 1000 patients

10%

LIPID Study Group, NEJM, 1998LIPID Study Group, NEJM, 1998LIPID Study Group, NEJM, 1998LIPID Study Group, NEJM, 1998

LIPID Trial LIPID Trial Statin Therapy for Patients with Recent ACSStatin Therapy for Patients with Recent ACS

6/046/04

0

0.05

0.1

0.15

0.2

0 500 1000 1500

Days of Follow-up

% D

ea

th, M

I, o

r S

tro

ke

Ramipril Placebo

HOPE Primary Results HOPE Primary Results Broad Benefits of ACE InhibitorsBroad Benefits of ACE Inhibitors

p<0.001

6/046/04

Risk Factor ModificationRisk Factor Modification

Smoking Cessation CounselingSmoking Cessation Counseling

Dietary Counseling and ModificationDietary Counseling and Modification

Cardiac Rehabilitation ReferralCardiac Rehabilitation Referral

HTN Control (BP < 130/85 mm Hg)HTN Control (BP < 130/85 mm Hg)

Tight Glycemic Control in DiabeticsTight Glycemic Control in Diabetics

Smoking Cessation CounselingSmoking Cessation Counseling

Dietary Counseling and ModificationDietary Counseling and Modification

Cardiac Rehabilitation ReferralCardiac Rehabilitation Referral

HTN Control (BP < 130/85 mm Hg)HTN Control (BP < 130/85 mm Hg)

Tight Glycemic Control in DiabeticsTight Glycemic Control in Diabetics

II IIaIIa IIbIIb IIIIII