New Treatment Advances in Acute Coronary Syndrome.

New Treatment AdvancesNew Treatment Advancesin Acute Coronaryin Acute CoronarySyndromeSyndrome

ObjectivesObjectives

• Establish that ACS (unstable angina/non–ST-Establish that ACS (unstable angina/non–ST-elevation MI) is a high-risk conditionelevation MI) is a high-risk condition

• Present the identified barriers to GP IIb/IIIa usePresent the identified barriers to GP IIb/IIIa use

• Identify patients that benefit from GP IIb/IIIa therapyIdentify patients that benefit from GP IIb/IIIa therapy

• Conclusion:Conclusion:

– Establish the need and rationale for early treatment Establish the need and rationale for early treatment with GP IIb/IIIa therapywith GP IIb/IIIa therapy

Risk of ACSRisk of ACSClinical Outcomes at 30 Days in Standard Care ArmClinical Outcomes at 30 Days in Standard Care Arm

15.7%

11.9%

11.7%

8.98%

7.7%

0 5 10 15 20

PURSUIT

PRISM-PLUS

PARAGON

CAPTURE

ESSENCE

Risk of Death or MIRisk of Death or MI

Cohen M, et al. Cohen M, et al. N Engl J MedN Engl J Med. 1997;337:447–452.. 1997;337:447–452.

Kong DF, et al. Kong DF, et al. CirculationCirculation. 1998;98:2829–2835.. 1998;98:2829–2835.

GP IIb/IIIa Inhibitor Utilization in GP IIb/IIIa Inhibitor Utilization in 19991999

7%

93%IIb/IIIaNo IIb/IIIa

PCI ACS

Internal Merck Market Research, 1999.

54%

46%

The Role of Platelets in ACSThe Role of Platelets in ACS

Recruitment Recruitment and Activationand Activation

Adapted from Schafer AI. Adapted from Schafer AI. Am J MedAm J Med. 1996;101:199–209.. 1996;101:199–209.

AdhesionAdhesion AggregationAggregation

Fibrin Fibrin strandstrand

PlateletsPlatelets

SubendotheliumSubendotheliumexposedexposed

ADPADPTXATXA22

GP IIb/IIIa Receptor Activation GP IIb/IIIa Receptor Activation PathwaysPathways

Current Limitations to the Use of Current Limitations to the Use of GP IIb/IIIa Inhibitors GP IIb/IIIa Inhibitors

• Physician perceptionsPhysician perceptions

– No incremental benefit beyond ASA-heparinNo incremental benefit beyond ASA-heparin

– Bleeding risk is unacceptableBleeding risk is unacceptable

• Not sure how patients will be treated: PTCA, Not sure how patients will be treated: PTCA, CABG, medical therapyCABG, medical therapy

• Use of LMWHUse of LMWH

• Not sure Not sure whomwhom to treat or to treat or whenwhen to treat to treat








Risk of ACSRisk of ACSClinical Outcomes at 30 Days in Standard Care ArmClinical Outcomes at 30 Days in Standard Care Arm

15.7%

11.9%

11.7%

8.98%

7.7%

0 5 10 15 20

PURSUIT

PRISM-PLUS

PARAGON

CAPTURE

ESSENCE

Risk of Death or MIRisk of Death or MI

Cohen M et al. Cohen M et al. N Engl J MedN Engl J Med. 1997:337:447–452.. 1997:337:447–452.

Kong DF et al. Kong DF et al. CirculationCirculation. 1998;98:2829–2835.. 1998;98:2829–2835.

Inclusion CriteriaInclusion Criteria

– Prolonged anginal pain at rest during previous 12 hours andProlonged anginal pain at rest during previous 12 hours and

– New transient or persistent ST-T changes orNew transient or persistent ST-T changes or

– Elevation of CK and CK-MBElevation of CK and CK-MB

Selected Exclusion CriteriaSelected Exclusion Criteria

– Patients with current or recent history of bleeding eventsPatients with current or recent history of bleeding events

– High blood pressureHigh blood pressure

– Persistent ST-elevationPersistent ST-elevation

Entry Criteria, Exclusion Criteria and Study Entry Criteria, Exclusion Criteria and Study Design: PRISM-PLUSDesign: PRISM-PLUS

PTCA

48 hour StudyDrug Theapy

ContinuedMedical Therapy

Presentation

Angiography(90% of Patients) CABG

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.


– Prolonged anginal pain at rest during previous 24 hours andProlonged anginal pain at rest during previous 24 hours and

– New transient or persistent ST-T changes orNew transient or persistent ST-T changes or

– Elevation of CK-MBElevation of CK-MB


– Patients with current or recent history of bleeding eventsPatients with current or recent history of bleeding events

– High blood pressureHigh blood pressure


Entry Criteria, Exclusion Criteria and Study Entry Criteria, Exclusion Criteria and Study Design: PURSUITDesign: PURSUIT

ContinuedMedical Therapy

Presentation

± Angiography

PTCA

CABG

Infusion of Study Drug

PURSUIT Trial Investigators. PURSUIT Trial Investigators. N Engl J Med.N Engl J Med. 1998;339:436–443. 1998;339:436–443.

0

5

10

15

20

25

2 Days 7 Days (primary endpoint)

30 Days

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

17.9

12.9

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

22.3

18.5

% P

atie

nts

% P

atie

nts

The PRISM-PLUS Study Investigators. The PRISM-PLUS Study Investigators. N Engl J MedN Engl J Med. 1998;338:1488. 1998;338:1488–1497.1497.

Heparin (n=797)

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

NSNSPP=0.08=0.08

7.85.7

PRISM-PLUS: Composite MI/Death/Refractory PRISM-PLUS: Composite MI/Death/Refractory Ischemia Event Rates at 2, 7, and 30 DaysIschemia Event Rates at 2, 7, and 30 Days

0

5

10

15

2 Days 7 Days 30 Days

RR=43%P=0.006

8.3

4.9

RR=30%P=0.03

11.9

8.7

% P

atie

nts

% P

atie

nts


Heparin (n=797)

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

RR=66%P=0.01

2.6

0.9

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


RR=32%P=0.004

Composite Endpoint

RefractoryIschemia

MI/Death

RR=30%P=0.02

RR=47%P=0.006

RR=43%P=0.006

MI

P=0.99

Death

% P

ati

ents

% P

ati

ents

Heparin (N=797)

AGGRASTAT® (tirofiban HCI)+ Heparin (N=773)

0

5

10

15

20

PRISM-PLUS:PRISM-PLUS:Event Rates at 7 DaysEvent Rates at 7 Days

PURSUIT Trial: 96 hrs, 7 and 30 Day Rates of PURSUIT Trial: 96 hrs, 7 and 30 Day Rates of MI/DeathMI/Death

9.1

11.6

15.7

7.6

10.1

14.2

0

2

4

6

8

10

12

14

16

18

96 Hours 7 Days 30 Days

Eve

nt

Rat

e %

Ch

ang

e

PlaceboEptifibatide

PURSUIT Investigators. PURSUIT Investigators. N Engl J Med.N Engl J Med. 1998;339:436 1998;339:436–443. Adapted from Table 2.443. Adapted from Table 2.

P = 0.04

P = 0.02

P = 0.01

(Primary Endpoint)

Conclusion:Conclusion:

• PRISM-PLUS (tirofiban) demonstrated a significant PRISM-PLUS (tirofiban) demonstrated a significant reduction in the primary endpoint.reduction in the primary endpoint.

• PURSUIT (eptifibatide) demonstrated a significant PURSUIT (eptifibatide) demonstrated a significant reduction in the primary endpoint.reduction in the primary endpoint.

• Short-acting GP IIb/IIIa Inhibitors reduce events in Short-acting GP IIb/IIIa Inhibitors reduce events in unstable angina/nonunstable angina/non––Q-wave MI patients.Q-wave MI patients.








Major Bleeding (TIMI)

Minor Bleeding (TIMI)

Transfusions (all blood products)

Platelets 90,000/mm3

1.4%

10.5%

4.0%

1.9%

0.8%

8.0%

2.8%

0.8%

AGGRASTATAGGRASTAT ®®

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

HeparinHeparinn=797n=797

PRISM-PLUS: Hematologic PRISM-PLUS: Hematologic ComplicationsComplications

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.

nn %%

AGGRASTAT AGGRASTAT ®® (tirofiban HCl) (tirofiban HCl) + Heparin+ Heparin HeparinHeparin

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

Interventional ProceduresInterventional Procedures

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

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

Contraindications for AGGRASTATContraindications for AGGRASTAT® ®

(tirofiban HCl)(tirofiban HCl)AGGRASTAT is contraindicated in patients withAGGRASTAT is contraindicated in patients with

• Known hypersensitivity to any component of the productKnown hypersensitivity to any component of the product

• Active internal bleeding or a history of bleeding diathesis within the previous Active internal bleeding or a history of bleeding diathesis within the previous 30 days30 days

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

• History of thrombocytopenia following prior exposure to AGGRASTATHistory of thrombocytopenia following prior exposure to AGGRASTAT

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

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

• History, symptoms, or findings suggestive of aortic dissectionHistory, symptoms, or findings suggestive of aortic dissection

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

• Concomitant use of another parenteral GP IIb/IIIa inhibitorConcomitant use of another parenteral GP IIb/IIIa inhibitor

• Acute pericarditisAcute pericarditis

Laboratory MonitoringLaboratory Monitoring

• Platelet counts, hemoglobin, and hematocrit should be monitored Platelet counts, hemoglobin, and hematocrit should be monitored prior to treatment, within 6 hours following the loading infusion, prior to treatment, within 6 hours following the loading infusion, and at least daily thereafter during therapy with AGGRASTATand at least daily thereafter during therapy with AGGRASTAT®® (tirofiban HCl).(tirofiban HCl).

• If the patient experiences a platelet decrease to If the patient experiences a platelet decrease to <90,000/mm<90,000/mm33, additional platelet counts should be performed to , additional platelet counts should be performed to exclude pseudothrombocytopenia.exclude pseudothrombocytopenia.

• If thrombocytopenia is confirmed, AGGRASTAT and heparin should If thrombocytopenia is confirmed, AGGRASTAT and heparin should be discontinued and the condition appropriately monitored and be discontinued and the condition appropriately monitored and treated.treated.

• To monitor unfractionated heparin, aPTT should be monitored 6 To monitor unfractionated heparin, aPTT should be monitored 6 hours after the start of heparin infusion; heparin should be hours after the start of heparin infusion; heparin should be adjusted to maintain aPTT at approximately 2 times control.adjusted to maintain aPTT at approximately 2 times control.








0

5

10

15

20

25

30

35Heparin Tirofiban + Heparin

Medical Rx PTCA CABG

16.814.8

24.2

18

33.2

28.7RR=13%

RR=32%

RR=20%

GP IIb/IIIa Inhibition: GP IIb/IIIa Inhibition: Composite Endpoint at 30 Days by Treatment Composite Endpoint at 30 Days by Treatment

Strategy in PRISM-PLUS*Strategy in PRISM-PLUS*

* Post-randomization analysis. Data available on File DA-AGG06(2)

0

5

10

15

20Heparin Tirofiban + Heparin

Medical Rx PTCA CABG

10.1

7.8

13.1

8.8

16.8

12.2

RR=25%RR=25%

RR=34%RR=34%

RR=30%RR=30%

GP IIb/IIIa Inhibition: GP IIb/IIIa Inhibition: Death or MI at 30 Days by Treatment Strategy Death or MI at 30 Days by Treatment Strategy

in PRISM-PLUS*in PRISM-PLUS*

* Post-randomization analysis. Data available on File DA-AGG06(2)









– Anginal pain at rest during previous 24 hours andAnginal pain at rest during previous 24 hours and

– New ST-T wave changes orNew ST-T wave changes or

– previous MI or revascularization orprevious MI or revascularization or

– results of invasive or non-invasive testing suggesting ischemic heart results of invasive or non-invasive testing suggesting ischemic heart diseasedisease


– Contraindications to anticoagulationContraindications to anticoagulation


Study DesignStudy Design

– Patients randomized to enoxaparin or unfractionated heparin for 2–8 Patients randomized to enoxaparin or unfractionated heparin for 2–8 days.days.

Entry Criteria, Exclusion Criteria and Study Entry Criteria, Exclusion Criteria and Study Design: ESSENCEDesign: ESSENCE

Cohen M et al. Cohen M et al. N Engl J MedN Engl J Med. 1997;337:447–452.. 1997;337:447–452.

1 2 14 30

% o

f P

atie

nts

Wit

h E

ven

ts%

of

Pat

ien

ts W

ith

Eve

nts

Days From RandomizationDays From Randomization

P = 0.019 P = 0.01623.3%

19.8%

Heparin, N=1564Enoxaparin, N=1607

15%

Adapted from Cohen M, et al. Adapted from Cohen M, et al. N Engl J MedN Engl J Med. 1997;337:447–452.. 1997;337:447–452.

0.30

0.25

0.20

0.15

0.10

0.05

0.00

ESSENCE: Enoxaparin in UA/NQWMIESSENCE: Enoxaparin in UA/NQWMICumulative Events at 14 Days:Cumulative Events at 14 Days:Death, MI, Recurrent AnginaDeath, MI, Recurrent Angina

19.8%

16.6%

Primary Endpoint

6.2%

7.4%P = 0.18

Treating Acute Coronary Treating Acute Coronary Syndrome Prior to Syndrome Prior to CatheterizationCatheterization







• Not sureNot sure whomwhom to treat to treat or or whenwhen to treat to treat

Ischemic Chest Pain Ischemic Chest Pain Non–ST-Elevation ACSNon–ST-Elevation ACS

• Heparin and aspirinHeparin and aspirin• Glycoprotein IIb/IIIa inhibitorGlycoprotein IIb/IIIa inhibitor • NitratesNitrates• -Blocker-Blocker

Positive MarkersPositive Markers

ST Depression ST Depression 1mm 1mm

Dynamic ECG Dynamic ECG

or

or

PRISM-PLUS: Consistency of PRISM-PLUS: Consistency of Risk ReductionsRisk 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%

AGGRASTATAGGRASTAT (tirofiban HCI) (tirofiban HCI) RiskRisknn HeparinHeparin + Heparin+ Heparin ReductionReduction

Prognostic Value of ECG Changes: GUSTO IIbPrognostic Value of ECG Changes: GUSTO IIb

Days From Randomization

Mo

rtal

ity,

%ST-Segment Elevation and DepressionST-Segment DepressionST-Segment ElevationIsolated T-Wave Inversion

Adapted from Savonitto S, et al. Adapted from Savonitto S, et al. JAMAJAMA. 1999;281:707-713.. 1999;281:707-713.

10

9

8

7

6

5

4

3

2

1

0 20 40 60 80 100 120 140 160 180

P 0.001

Conclusion: TnI has important prognostic value for patients with unstable angina

Adapted from Galvani M, et al. Adapted from Galvani M, et al. CirculationCirculation. 1997; 95:2053–2059.. 1997; 95:2053–2059.

5.8%

27.3%

0

5

10

15

20

25

P=0.02

Co

mp

osi

te E

nd

po

int

(30

day

s -

MI,

Dea

th)

TnI-n = 69

TnI+n = 22

Cardiac Endpoints in Unstable AnginaCardiac Endpoints in Unstable AnginaTroponin I in CK-MB Negative Patients with ECG Troponin I in CK-MB Negative Patients with ECG

ChangesChanges

30

Adapted from Armstrong PW, et al. Adapted from Armstrong PW, et al. Circulation.Circulation. 1998;98:1860–1868. 1998;98:1860–1868.

Prognostic Value of Refractory Ischemia Prognostic Value of Refractory Ischemia in Patients Without ST-Segment Elevation: GUSTO IIbin Patients Without ST-Segment Elevation: GUSTO IIb

Cumulative SurvivalCumulative Survival30-Day Infarction 30-Day Infarction

0

5

10

15

20

25

30

2.6%2.6%

9.2%9.2%

25.4%25.4%

%

1.00

DaysDays

.95

.90

.85

.80

.75

.70

60 120 180 240 300 3600

No Recurrent IschemiaNo Recurrent Ischemia Nonrefractory IschemiaNonrefractory Ischemia

Refractory IschemiaRefractory Ischemia

P<0.02

P<0.02








0.030

0.025

0.020

0.015

0.010

0.005

0.000

6 300 12 18 24 36 42 48

Heparin only

AGGRASTAT® (tirofiban HCl) + Heparin

RR = 66%

All 1570 Patients Evaluated

Hours

Pro

bab

ilit

y o

f D

eath

o

r M

I


PRISM-PLUS: Combined MI and Death PRISM-PLUS: Combined MI and Death During Initial 48 Hours in All PatientsDuring Initial 48 Hours in All Patients

Thrombus (N=643)

No Thrombus (N=784)

% P

atie

nts

Wit

h E

ven

t%

Pat

ien

ts W

ith

Eve

nt

0

5

15

10

20

Composite Refr. Ischemia MI DeathMI/Death

2%

20%*

10%

4%

12%*

6%

9%* 9%*

5%*5%

Events at 30 DaysEvents at 30 Days

* * PP<0.005<0.005..Adapted from Zhao XQ, et al. Adapted from Zhao XQ, et al. CirculationCirculation. 1999;100:1609–1615.. 1999;100:1609–1615.

Intracoronary Thrombus as a Predictor of Clinical Intracoronary Thrombus as a Predictor of Clinical Outcomes in Unstable Angina/NQWMIOutcomes in Unstable Angina/NQWMI

Recent Occlusion

PRISM-PLUS: Thrombus GradePRISM-PLUS: Thrombus Grade

Adapted from Zhao XQ, et al. Adapted from Zhao XQ, et al. CirculationCirculation. 1999;100:1609–1615.. 1999;100:1609–1615.

0

10

20

30

40

50

Cu

mu

lativ

e %

Cu

mu

lativ

e %

Heparin(n=622)

LargeRecent Occlusion

Tirofiban + Heparin(n=608)

Possible

Small

Moderate

Possible

Small

Moderate

OverallOdds Ratio:

0.77P=0.022

17.1%24.1%

Large

TIMI Flow as a Predictor of Clinical Outcomes in UAP/NQWMI

0

5

10

15

20

25

30 TIMI 0-2 (n=298) TIMI 3 (n=1095)

% P

atie

nts

Wit

h E

ven

t

20%

12%

5%

9%

Composite Refr. Ischemia MIMI/Death

6%10%

7.4% 5.5%

Events at 30 Days


PRISM-PLUS: TIMI FlowPRISM-PLUS: TIMI Flow


0

5

10

15

20

25

Cu

mu

lativ

e %

Cu

mu

lativ

e %

MinimalPerfusion(TIMI 1)

Heparin(n=580)

Totalocclusion

(TIMI 0)

Partialperfusion(TIMI 2)

Totalocclusion

(TIMI 0)

Partialperfusion(TIMI 2)

OverallOverallOdds Ratio:Odds Ratio:

0.650.65

PP=0.002=0.00218.1%

25.5%

Tirofiban + Heparin(n=570)

Acute Coronary Syndrome SummaryAcute Coronary Syndrome Summary

• Major adverse cardiac event rates are substantial despite therapy with aspirin and heparin.

• Studies show that therapy with GP IIb/IIIa inhibitors in combination with aspirin and heparin reduce the risk of adverse outcomes

– In patients with objective evidence of ischemia (ST depression, positive markers, dynamic ECG changes)

• GP IIb/IIIa inhibitors have an acceptable safety profile.

• Currently only 7% of ACS patients eligible for GP IIb/IIIa therapy are being treated.

Before prescribing AGGRASTAT® (tirofiban HCl), please read the complete Prescribing Information available at this presentation.

AGGRASTAT is a registered trademark of Merck & Co., Inc.© 2000 Merck & Co., Inc. All rights reserved. 003235(1)-05-AGG

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New Treatment Advances in Acute Coronary Syndrome.

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