Incidence of Acute Coronary Syndromes (ACS): Statistics From Various Studies 1.4 million hospitalizations each year for ACS 944,000 hospitalizations for

Incidence of Acute Coronary Syndromes (ACS): Incidence of Acute Coronary Syndromes (ACS): Statistics From Various StudiesStatistics From Various Studies

• 1.4 million hospitalizations each year for ACS

• 944,000 hospitalizations for unstable angina; 1994

• 121,000 hospitalizations for non–Q-wave MI; 1994

60% patients with unstable angina >65 years old

• 46% of patients with unstable angina are women

Hochman JS et al. Hochman JS et al. J Am Coll CardiolJ Am Coll Cardiol. 1997;30:141-148; . 1997;30:141-148; Vital and Health StatisticsVital and Health Statistics. Hyattsville, Md: . Hyattsville, Md: 1994: Series 13, No. 127; 1994: Series 13, No. 127; Clinical Practice GuidelinesClinical Practice Guidelines. AHCPR publication No. 94-0602.. AHCPR publication No. 94-0602.

Clinical Trials of Unstable Angina and Clinical Trials of Unstable Angina and NQWMI: Short-Term MortalityNQWMI: Short-Term Mortality

The TIMI IIIB Investigators. The TIMI IIIB Investigators. Circulation.Circulation. 1994;89:1545-1556; Cohen M et al. 1994;89:1545-1556; Cohen M et al. J Am Coll Cardiol. J Am Coll Cardiol. 1993;32:1338-1343; Lindahl B et al. 1993;32:1338-1343; Lindahl B et al. Circulation. Circulation. 1996;93:1651-1657.1996;93:1651-1657.

0

2

4

6

8

10

12

TIMI IIIB FRISC ATACS1407 976 330

6 weeks 5 months 12 weeksN =F/U =

Unstable AnginaUnstable Angina

NQWMINQWMI

% M

orta

lity

Clinical Trials of Unstable Angina and Clinical Trials of Unstable Angina and NQWMI: Short-Term Risk of MINQWMI: Short-Term Risk of MI

The TIMI IIIB Investigators. The TIMI IIIB Investigators. Circulation.Circulation. 1994;89:1545-1556; Cohen M et al. 1994;89:1545-1556; Cohen M et al. J Am Coll Cardiol. J Am Coll Cardiol. 1993;32:1338-1343; FRISC Study Group. 1993;32:1338-1343; FRISC Study Group. Lancet. Lancet. 1996;347:561-568; Klein W et al. 1996;347:561-568; Klein W et al. CirculationCirculation. . 1997;96(1):61-68; Cohen M et al. 1997;96(1):61-68; Cohen M et al. N Engl J MedN Engl J Med. 1997;337:447-452.. 1997;337:447-452.

6.5%

4.0%

11.0%

5.5%

3.4%

8.1%

4.5%

0

2

4

6

8

10

12

TIMI IIIB ATACS ESSENCE FRISC FRIC

Unstable Angina Pectoris(UAP)

NQWMI

UAP+NQWMI

% In

cid

ence

MI

% In

cid

ence

MI

6 Weeks 12 Weeks 30 Days 40 Days 45 DaysF/U =

Ischemic Heart Disease: Ischemic Heart Disease: Time-Dependent Mortality RiskTime-Dependent Mortality Risk

0

5

10

15

20

25

0 1 2 3 4 5 6

De

ath

s/1

00

Pts

/Mon

thD

ea

ths/

10

0 P

ts/M

onth

Months After Hospital AdmissionMonths After Hospital Admission

Acute MIAcute MI

Unstable AnginaUnstable Angina

Stable AnginaStable Angina

Clinical Practice Guidelines.Clinical Practice Guidelines. AHCPR publication No. 94-0602. AHCPR publication No. 94-0602.

Determinants of Plaque VulnerabilityDeterminants of Plaque Vulnerability

Downstream Downstream embolizationembolization

DETERMINANTS OF DETERMINANTS OF THROMBOSIS THROMBOSIS - Local factors- Local factors- Systemic factors- Systemic factors

UNSTABLE CORONARYUNSTABLE CORONARY ARTERY DISEASEARTERY DISEASE

RecanalizationRecanalization

LysisLysis

Remodeling

Remodeling

DYNAMIC

Lysis/

Repair

Lysis/

Repair

Cap disruptionCap disruption- Vulnerability- Vulnerability- Triggers- Triggers

VULNERABLE PLAQUEVULNERABLE PLAQUE

Fibrous capFibrous cap

Inflammation and repairInflammation and repair

Core sizeCore size

Lipid-rich coreLipid-rich core

Thr

ombo

lysi

s Throm

bosis

Fibrous tissue

Atheromatous material(lipid-rich)

Thrombus

Plaque hemorrhage

Macrophage

Smooth muscle cell

Theroux P, Fuster V. Theroux P, Fuster V. CirculationCirculation. 1998;97:1195-1206.. 1998;97:1195-1206.

CapCapthicknessthickness

LumenLumen

AGGRASTATAGGRASTAT (tirofiban HCl): Profile (tirofiban HCl): Profile

• Nonpeptide tyrosine derivative with MW 495 kD• Short-acting, reversible intravenous agent

– Upon discontinuation of AGGRASTAT, platelet function returns to near baseline within 4-8 hours in 90% of patients

• Nonpeptide inhibitor of platelet GP IIb/IIIa receptor• Blocks fibrinogen binding, inhibits aggregation• High specificity for receptor

HN CH2CH2CH2CH2O

COOH

HNHSO2CH2CH2CH2CH3

CH2

C• HCI • H2O

AGGRASTAT Prescribing Information.AGGRASTAT Prescribing Information.

Indications for AGGRASTATIndications for AGGRASTAT®® (tirofiban HCl) (tirofiban HCl)

• AGGRASTAT, in combination with heparin, is indicated for the treatment of ACS, including patients who are to be managed medically and those undergoing PTCA or atherectomy. In this setting, AGGRASTAT has been shown to decrease the rate of a combined endpoint of death, new myocardial infarction or refractory ischemia/repeat cardiac procedure.


Contraindications for Contraindications for AGGRASTATAGGRASTAT

®® (tirofiban HCl) (tirofiban HCl)

AGGRASTAT is contraindicated in patients with:

• Known hypersensitivity to any component of the product

• Active internal bleeding or a history of bleeding diathesis within the previous 30 days

• History of intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm

• History of thrombocytopenia following prior exposure to AGGRASTAT

• History of stroke within 30 days or any history of hemorrhagic stroke

• Major surgical procedure or severe physical trauma within the previous month

• History, symptoms, or findings suggestive of aortic dissection

• Severe hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg)

• Concomitant use of another parenteral GP IIb/IIIa inhibitor

• Acute pericarditis


PRISMPRISM

PRISM-PLUSPRISM-PLUS

MedicalStabilization

ContinuedMedical Therapy

Presentation

± Angiography

Clinical Program for AGGRASTATClinical Program for AGGRASTAT

®®(tirofiban HCl) (tirofiban HCl)

in UAP/NQWMIin UAP/NQWMI

The PRISM Study Investigators. The PRISM Study Investigators. N Engl J MedN Engl J Med. 1998;338:1498-1505.. 1998;338:1498-1505.The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.The RESTORE Investigators. The RESTORE Investigators. CirculationCirculation. 1997;96:1445-1453.. 1997;96:1445-1453.

RESTORERESTORE

PTCA

CABG

PRISM-PLUS: Entry CriteriaPRISM-PLUS: Entry Criteria

• 1915 patients with UAP or NQWMI randomized

• Entry criteria– Prolonged anginal pain or repetitive episodes of angina

at rest or during minimal exercise in previous 12 h and– New transient or persistent ST-T ischemic changes on

the ECG or– Elevation of plasma CK and CK-MB– 1570 patients evaluated

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497.. 1998;338:1488-1497.

PRISM-PLUS: Exclusion CriteriaPRISM-PLUS: Exclusion CriteriaPatients were excluded from the study if they had

• ST-segment elevation >20 min

• Thrombolysis in previous 48 h

• Coronary angioplasty within the previous 6 mo or bypass surgery within the previous 1 mo

• Angina caused by identifiable factors

• History of a platelet disorder or thrombocytopenia

• Active bleeding or a high risk of bleeding

• Stroke within the previous year

• Serum creatinine >2.5 mg/dL or platelets <150,000/mm3


Angiography+ PTCA

Hour 0 96 108 Day 7

Study Drug

Day 30

Primary Primary EndpointEndpoint

Secondary Endpoint

Secondary Endpoint

Day 180

PrespecifiedLong-termFollow-up

Random-ization

48

PRISM-PLUS: Study DesignPRISM-PLUS: Study Design


0

5

10

15

20

PRISM-PLUS: Event Reductions at 7 DaysPRISM-PLUS: Event Reductions at 7 Days

RR=32%RR=32%PP=0.004=0.004

Composite Endpoint

RefractoryIschemia

MI/Death

RR=30%RR=30%PP=0.02=0.02

RR=47%RR=47%PP=0.006=0.006

RR=43%RR=43%PP=0.006=0.006

MI


PP=0.99=0.99

Death

% P

atie

nts

% P

atie

nts

Heparin (n=797)

AGGRASTAT® (tirofiban HCl) + Heparin (n=773)

PRISM-PLUS: Composite Endpoint PRISM-PLUS: Composite Endpoint at 2, 7, and 30 Daysat 2, 7, and 30 Days

0

5

10

15

20

25

PP=NS=NS

RR=32%RR=32%PP=0.004=0.004

RR=22%RR=22%PP=0.029=0.029

2 Days 7 Days 30 Days


7.87.85.75.7

17.917.9

12.912.9

22.322.3

18.518.5

% P

atie

nts

% P

atie

nts

Heparin (n=797)


PRISM-PLUS: Combined MI/Death Event PRISM-PLUS: Combined MI/Death Event Reductions at 2, 7, and 30 DaysReductions at 2, 7, and 30 Days

RR=66%RR=66%PP=0.01=0.01

2 Days 7 Days

RR=43%RR=43%PP=0.006=0.006

RR=30%RR=30%PP=0.03=0.03

30 Days

2.62.60.90.9

8.38.3

4.94.9

11.911.9

8.78.7

% P

atie

nts

% P

atie

nts


Heparin (n=797)


DayDay

PRISM-PLUS: Composite Endpoint (180 Days)PRISM-PLUS: Composite Endpoint (180 Days)


5

10

15

20

25

% W

ith E

ndp

oin

t%

With

En

dpo

int

HeparinHeparin

AGGRASTATAGGRASTAT®® (tirofiban HCl) (tirofiban HCl)+ Heparin+ Heparin

= -5.0%, RR=32%, P=0.004

0 30 60 90 120 150 1807

= -3.8%, RR=22%, P=0.029

= -4.4%, RR=19%, P=0.02

30

35

Day

2

4

6

8

10

12

14

16

18

% W

ith E

ndp

oin

t%

With

En

dpo

int

HeparinHeparin


= -3.0%

P=0.06= -3.2%

P=0.03

=-3.4%, RR=43%, P=0.006

0 30 60 90 120 150 1807

RR=30%

RR=22%

PRISM-PLUS: Combined MI/Death (180 Days)PRISM-PLUS: Combined MI/Death (180 Days)


0

5

10

15

PRISM-PLUS: Composite Endpoint at 30 Days in PRISM-PLUS: Composite Endpoint at 30 Days in Patients Treated MedicallyPatients Treated Medically

RR=13%RR=13%


16.8%16.8%14.8%14.8%

% P

atie

nts

% P

atie

nts

Heparin (n=375)


10

20

0

5

10

15

PRISM-PLUS: Combined MI/Death Outcomes PRISM-PLUS: Combined MI/Death Outcomes at 30 Days in Patients Treated Medicallyat 30 Days in Patients Treated Medically

RR=25%RR=25%


10.1%10.1%

7.8%7.8%

% P

atie

nts

% P

atie

nts

Heparin (n=375)


Heparin (n=236)


PRISM-PLUS: Composite EndpointPRISM-PLUS: Composite Endpoint at 30 Days at 30 Days Among Patients Undergoing PTCAAmong Patients Undergoing PTCA


0

5

10

15

RR=32%RR=32%

24.2%24.2%

18.0%18.0%%

Pa

tien

ts%

Pa

tien

ts20

25

0

5

10

15

Heparin (n=236)

AGGRASTAT® (tirofiban HCI) + Heparin (n=239)

PRISM-PLUS: Combined MI/Death Outcomes PRISM-PLUS: Combined MI/Death Outcomes at 30 Days Among Patients Undergoing at 30 Days Among Patients Undergoing PTCAPTCA

RR=34%RR=34%

13.1%13.1%

8.8%8.8%

% P

atie

nts

% P

atie

nts


PRISM-PLUS: Composite Endpoint Following PTCAPRISM-PLUS: Composite Endpoint Following PTCA

= -6.2%

0 30 60 90 120 150 180Day

4

8

12

16

20

24

28

32

% W

ith E

ndp

oin

t%

With

En

dpo

int HeparinHeparin


= -6.5%RR=45%

RR=27%

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488-1497. . 1998;338:1488-1497. DA-AGG08. Available on request from Merck & Co., Inc.DA-AGG08. Available on request from Merck & Co., Inc.

PRISM-PLUS: Composite Endpoint at 30 Days Among PRISM-PLUS: Composite Endpoint at 30 Days Among Patients Who Underwent CABG Subsequent to Patients Who Underwent CABG Subsequent to Treatment With AGGRASTATTreatment With AGGRASTAT

®® (tirofiban HCl) (tirofiban HCl)

DA-AGG06. Available on request from Merck & Co., Inc.DA-AGG06. Available on request from Merck & Co., Inc.

Heparin (n=184)AGGRASTAT+ Heparin (n=181)

0

RR=20%RR=20%

33.2%33.2%

28.7%28.7%%

Pat

ient

s%

Pat

ient

s

5

10

15

20

25

30

35

PRISM-PLUS: Combined MI/Death Outcomes at 30 Days PRISM-PLUS: Combined MI/Death Outcomes at 30 Days Among Patients Who Underwent CABG Subsequent to Among Patients Who Underwent CABG Subsequent to

Treatment With AGGRASTATTreatment With AGGRASTAT ®® (tirofiban HCl) (tirofiban HCl)


Heparin (n=184)

AGGRASTAT + Heparin (n=181)

RR=30%RR=30%

16.8%16.8%

12.2%12.2%%

Pat

ient

s%

Pat

ient

s

0

5

10

15

20


PRISM-PLUS: Consistency of Risk ReductionsPRISM-PLUS: Consistency of Risk Reductions

Age (y)

<65 804 12.4% 8.5% 36%

65 766 23.5% 17.8% 30%

Gender

Female 506 19.0% 13.4% 33%

Male 1054 17.4% 12.7% 32%

nn HeparinHeparinAGGRASTATAGGRASTAT®® (tirofiban HCl) (tirofiban HCl)

+ Heparin+ HeparinRisk Risk

ReductionReduction

Percent of Patients Experiencing Composite Endpoint at 7 DaysPercent of Patients Experiencing Composite Endpoint at 7 Days

PRISM-PLUS: Combined MI and Death During PRISM-PLUS: Combined MI and Death During Initial 48 Hours in All Patients and Postprocedure Initial 48 Hours in All Patients and Postprocedure in Patients Undergoing PTCAin Patients Undergoing PTCA

2 4 14 21 287

0.12

0.08

0.04

0.00

Heparin onlyHeparin only

RR = 44%RR = 44%

475 Patients Undergoing PTCA475 Patients Undergoing PTCA

0.030

0.025

0.020

0.015

0.010

0.005

0.000

6 300 12 18 24 36 42 48

Heparin onlyHeparin only

AGGRASTATAGGRASTAT®® (tirofiban HCl) (tirofiban HCl) + Heparin+ Heparin

RR = 66%RR = 66%

All 1570 Patients EvaluatedAll 1570 Patients Evaluated

HoursHours DaysDays

Drug InfusionDrug InfusionPTCAPTCA

Pro

babi

lity

of D

eath

or

MI

Pro

babi

lity

of D

eath

or

MI



Major Bleeding (TIMI)Intracranial bleeding

Minor Bleeding (TIMI)

Transfusions (All blood products)

Platelets 90,000/mm3

1.4%0.0%

10.5%

4.0%

1.9%

0.8%0.0%

8.0%

2.8%

0.8%

AGGRASTATAGGRASTAT ®®

(tirofiban HCl) + Heparin(tirofiban HCl) + Heparinn=773n=773

HeparinHeparinn=797n=797

PRISM-PLUS: Hematologic ComplicationsPRISM-PLUS: Hematologic Complications


nn %%

AGGRASTATAGGRASTAT ®® (tirofiban HCl) (tirofiban HCl)

+ Heparin+ Heparin HeparinHeparin

PRISM-PLUS: Incidence of TIMI Major Bleeding in PRISM-PLUS: Incidence of TIMI Major Bleeding in Patients Undergoing Interventional ProceduresPatients Undergoing Interventional Procedures


nn %%

Prior to procedures 2/773 0.3 1/797 0.1

Following angiography 9/697 1.3 5/708 0.7

Following PTCA 6/239 2.5 5/236 2.2

Patients undergoing 5/29 17.2 11/31 35.4CABG*

* Within 1 day after discontinuation of AGGRASTAT.

PRISM-PLUS: Angiographic SubstudyPRISM-PLUS: Angiographic Substudy

• Objective: Effect of AGGRASTAT® (tirofiban HCl) on angiographically apparent thrombus

• Films prior to hour 97 analyzed by blinded Core Laboratory

• 1230 films readable and analyzed (608 in AGGRASTAT + heparin group; 622 in heparin group)


PRISM-PLUS: Thrombus GradePRISM-PLUS: Thrombus Grade


0

10

20

30

40

50C

um

ula

tive

%C

um

ula

tive

%

Heparin(n=622)

LargeRecent Occlusion

AGGRASTAT® (tirofiban HCl) + Heparin(n=608)

Possible

Small

Moderate

Possible

Small

Moderate

OverallOdds Ratio:

0.77P=0.022

17.1%24.1%

LargeRecent Occlusion

PRISM-PLUS: TIMI FlowPRISM-PLUS: TIMI Flow


0

5

10

15

20

25

Cu

mu

lativ

e %

Cu

mu

lativ

e %

MinimalPerfusion(TIMI 1)

AGGRASTAT® (tirofiban HCl) + Heparin(n=570)

Heparin(n=580)

TotalOcclusion

(TIMI 0)

PartialPerfusion(TIMI 2)

TotalOcclusion

(TIMI 0)

PartialPerfusion(TIMI 2)

OverallOdds Ratio:

0.65P=0.00218.1%

25.5%

RESTORE: Inclusion and Exclusion CriteriaRESTORE: Inclusion and Exclusion Criteria

The RESTORE Investigators. The RESTORE Investigators. CirculationCirculation. 1997;96:1445-1453.. 1997;96:1445-1453.

• Acute coronary syndrome within 72 hours– MI (Q-wave and NQWMI)– UAP

• Documentation– ECG ischemia or– CK elevation or– Angiographic thrombus

Inclusion Criteria

• Thrombolytic therapy within 24 hours• Contraindication to anticoagulation• History of platelet disorder or thrombocytopenia• History of stroke or other intracranial pathology predisposing to bleeding• Scheduled for elective stent placement or angioplasty using a rotablator or

transluminal extraction catheter device

Exclusion Criteria

Study Drug(10 g/kg bolus/0.15 g/kg/min infusion)

Prespecified Analyses

Hour 0 36 Day 2 Day 7 Day 30 Day 180

Primary Primary EndpointEndpoint

Secondary Endpoint

Randomization at Angioplasty/Atherectomy

RESTORE: Study DesignRESTORE: Study Design


RR=17%

RESTORE: Composite EndpointRESTORE: Composite Endpoint


0 5 10 15 20 25 30Day

0

3

6

9

12 Placebo + HeparinPlacebo + Heparin


=-3.3%

=-1.9%

=-2.8% P=0.17

P=0.023

P=0.004RR=38%

RR=28%

% W

ith C

om

po

site

En

dpo

int

% W

ith C

om

po

site

En

dpo

int

Major Bleeding (TIMI) Intracranial bleeding

Minor Bleeding (TIMI)

Transfusions (All blood products)

Platelets 90,000/mm3

Patients Undergoing CABGPatients Undergoing CABG

Major Bleeding (TIMI)

2.2%0.1%

12.0%

4.3%

1.1%

n=12n=12

25.0%

1.6%0.3%

6.3%

2.5%

0.9%

n=16n=16

37.5%

AGGRASTATAGGRASTAT ® ® (tirofiban HCl) (tirofiban HCl)

+ Heparin+ Heparinn=1071n=1071

HeparinHeparinn=1070n=1070

RESTORE: Hematologic ComplicationsRESTORE: Hematologic Complications

AGGRASTAT Prescribing Information.AGGRASTAT Prescribing Information.The RESTORE Investigators. The RESTORE Investigators. CirculationCirculation. 1997;96:1445-1453.. 1997;96:1445-1453.

All PatientsAll Patients

AGGRASTATAGGRASTAT®® (tirofiban HCl) (tirofiban HCl) Data SummaryData Summary

• Reversible, nonpeptide GP IIb/IIIa platelet receptor blocker

• Fast-on and fast-off antiplatelet effects

• Upon discontinuation of AGGRASTAT, platelet function returns to near baseline within 4-8 hours in 90% of patients

• Sustained clinical benefits (7, 30, and 180 days)

• Patients benefited regardless of treatment strategy (medical management, PTCA or CABG)

• Benefits were consistent regardless of patient’s age or gender

• Bleeding is the most common complication encountered during therapy with AGGRASTAT


Documents

Incidence of Acute Coronary Syndromes (ACS): Statistics From Various Studies 1.4 million hospitalizations each year for ACS 944,000 hospitalizations for