New Treatment Advances in Acute Coronary Syndrome

Objectives Establish that ACS (unstable angina/non–ST- elevation MI) is a high-risk condition Establish that ACS (unstable angina/non–ST- elevation MI) is a high-risk condition Present the identified barriers to GP IIb/IIIa use Present the identified barriers to GP IIb/IIIa use Identify patients that benefit from GP IIb/IIIa therapy Identify patients that benefit from GP IIb/IIIa therapy Conclusion: Conclusion: –Establish the need and rationale for early treatment with GP IIb/IIIa therapy

Risk of ACS Clinical Outcomes at 30 Days in Standard Care Arm Risk of Death or MI Cohen M, et al. N Engl J Med. 1997;337:447–452. Kong DF, et al. Circulation. 1998;98:2829–2835.

GP IIb/IIIa Inhibitor Utilization in 1999 PCI ACS Internal Merck Market Research, 1999.

The Role of Platelets in ACS Recruitment and Activation Adapted from Schafer AI. Am J Med. 1996;101:199–209. AdhesionAggregation Fibrin strand Platelets Subendothelium exposed ADP TXA 2

GP IIb/IIIa Receptor Activation Pathways

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Risk of ACS Clinical Outcomes at 30 Days in Standard Care Arm Risk of Death or MI Cohen M et al. N Engl J Med. 1997:337:447–452. Kong DF et al. Circulation. 1998;98:2829–2835.

Inclusion Criteria –Prolonged anginal pain at rest during previous 12 hours and –New transient or persistent ST-T changes or –Elevation of CK and CK-MB Selected Exclusion Criteria –Patients with current or recent history of bleeding events –High blood pressure –Persistent ST-elevation Entry Criteria, Exclusion Criteria and Study Design: PRISM-PLUS PTCA 48 hour Study Drug Theapy Continued Medical Therapy Presentation Angiography (90% of Patients) CABG The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488–1497.

Inclusion Criteria –Prolonged anginal pain at rest during previous 24 hours and –New transient or persistent ST-T changes or –Elevation of CK-MB Selected Exclusion Criteria –Patients with current or recent history of bleeding events –High blood pressure –Persistent ST-elevation Entry Criteria, Exclusion Criteria and Study Design: PURSUIT Continued Medical Therapy Presentation ± Angiography PTCA CABG Infusion of Study Drug PURSUIT Trial Investigators. N Engl J Med. 1998;339:436–443.

2 Days 7 Days (primary endpoint) 30 Days RR=32% P= RR=22% P= % Patients The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338: The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488 – Heparin (n=797) AGGRASTAT ® (tirofiban HCl) + Heparin (n=773) NS P= PRISM-PLUS: Composite MI/Death/Refractory Ischemia Event Rates at 2, 7, and 30 Days

2 Days7 Days 30 Days RR=43% P= RR=30% P= % Patients The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338: The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488 – Heparin (n=797) AGGRASTAT ® (tirofiban HCl) + Heparin (n=773) RR=66% P= PRISM-PLUS: Combined MI/Death Event Rates at 2, 7, and 30 Days

The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338: The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488 – RR=32% P=0.004 Composite Endpoint Refractory Ischemia MI/Death RR=30% P=0.02 RR=47% P=0.006 RR=43% P=0.006 MI P=0.99 Death % Patients Heparin (N=797) AGGRASTAT ® (tirofiban HCI) + Heparin (N=773) PRISM-PLUS: Event Rates at 7 Days

PURSUIT Trial: 96 hrs, 7 and 30 Day Rates of MI/Death PURSUIT Investigators. N Engl J Med. 1998;339: Adapted from Table 2. PURSUIT Investigators. N Engl J Med. 1998;339:436 – 443. Adapted from Table 2. P = 0.04 P = 0.02 P = 0.01 (Primary Endpoint)

Conclusion: PRISM-PLUS (tirofiban) demonstrated a significant reduction in the primary endpoint. PRISM-PLUS (tirofiban) demonstrated a significant reduction in the primary endpoint. PURSUIT (eptifibatide) demonstrated a significant reduction in the primary endpoint. PURSUIT (eptifibatide) demonstrated a significant reduction in the primary endpoint. Short-acting GP IIb/IIIa Inhibitors reduce events in unstable angina/non – Q-wave MI patients. Short-acting GP IIb/IIIa Inhibitors reduce events in unstable angina/non – Q-wave MI patients.

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Major Bleeding (TIMI) Minor Bleeding (TIMI) Transfusions (all blood products) Platelets  90,000/mm 3 1.4% 10.5% 4.0% 1.9% 0.8% 8.0% 2.8% 0.8% AGGRASTAT ® (tirofiban HCl) + Heparin n=773 Heparinn=797 PRISM-PLUS: Hematologic Complications The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:

n% AGGRASTAT ® (tirofiban HCl) + Heparin Heparin n% Prior to procedures2/ / Following angiography9/ / Following PTCA6/ / Patients undergoing5/ / CABG* * Within 1 day after discontinuation of AGGRASTAT. PRISM-PLUS: Incidence of TIMI Major Bleeding in Patients Undergoing Interventional Procedures

Indications for AGGRASTAT® (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 MI, or refractory ischemia/repeat cardiac procedure 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 MI, or refractory ischemia/repeat cardiac procedure

Contraindications for AGGRASTAT ® (tirofiban HCl) AGGRASTAT is contraindicated in patients with Known hypersensitivity to any component of the product Known hypersensitivity to any component of the product Active internal bleeding or a history of bleeding diathesis within the previous 30 days 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 intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, or aneurysm History of thrombocytopenia following prior exposure to AGGRASTAT History of thrombocytopenia following prior exposure to AGGRASTAT History of stroke within 30 days or any history of hemorrhagic stroke History of stroke within 30 days or any history of hemorrhagic stroke Major surgical procedure or severe physical trauma within the previous month Major surgical procedure or severe physical trauma within the previous month History, symptoms, or findings suggestive of aortic dissection History, symptoms, or findings suggestive of aortic dissection Severe hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg) Severe hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure >110 mmHg) Concomitant use of another parenteral GP IIb/IIIa inhibitor Concomitant use of another parenteral GP IIb/IIIa inhibitor Acute pericarditis Acute pericarditis

Laboratory Monitoring Platelet counts, hemoglobin, and hematocrit should be monitored prior to treatment, within 6 hours following the loading infusion, and at least daily thereafter during therapy with AGGRASTAT ® (tirofiban HCl). Platelet counts, hemoglobin, and hematocrit should be monitored prior to treatment, within 6 hours following the loading infusion, and at least daily thereafter during therapy with AGGRASTAT ® (tirofiban HCl). If the patient experiences a platelet decrease to <90,000/mm 3, additional platelet counts should be performed to exclude pseudothrombocytopenia. If the patient experiences a platelet decrease to <90,000/mm 3, additional platelet counts should be performed to exclude pseudothrombocytopenia. If thrombocytopenia is confirmed, AGGRASTAT and heparin should be discontinued and the condition appropriately monitored and treated. If thrombocytopenia is confirmed, AGGRASTAT and heparin should be discontinued and the condition appropriately monitored and treated. To monitor unfractionated heparin, aPTT should be monitored 6 hours after the start of heparin infusion; heparin should be adjusted to maintain aPTT at approximately 2 times control. To monitor unfractionated heparin, aPTT should be monitored 6 hours after the start of heparin infusion; heparin should be adjusted to maintain aPTT at approximately 2 times control.

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Medical RxPTCACABG RR=13% RR=32% RR=20% GP IIb/IIIa Inhibition: Composite Endpoint at 30 Days by Treatment Strategy in PRISM-PLUS* * Post-randomization analysis. Data available on File DA-AGG06(2)

Medical RxPTCACABG RR=25% RR=34% RR=30% GP IIb/IIIa Inhibition: Death or MI at 30 Days by Treatment Strategy in PRISM-PLUS* * Post-randomization analysis. Data available on File DA-AGG06(2)

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Inclusion Criteria –Anginal pain at rest during previous 24 hours and –New ST-T wave changes or –previous MI or revascularization or –results of invasive or non-invasive testing suggesting ischemic heart disease Selected Exclusion Criteria –Contraindications to anticoagulation –Persistent ST-elevation Study Design –Patients randomized to enoxaparin or unfractionated heparin for 2–8 days. Entry Criteria, Exclusion Criteria and Study Design: ESSENCE Cohen M et al. N Engl J Med. 1997;337:447–452. Cohen M et al. N Engl J Med. 1997;337:447–452.

% of Patients With Events Days From Randomization P = P = % 19.8% Heparin, N=1564 Enoxaparin, N= % Adapted from Cohen M, et al. N Engl J Med. 1997;337:447– ESSENCE: Enoxaparin in UA/NQWMI Cumulative Events at 14 Days: Death, MI, Recurrent Angina 19.8% 16.6% Primary Endpoint 6.2% 7.4% P = 0.18

Treating Acute Coronary Syndrome Prior to Catheterization

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Ischemic Chest Pain Non–ST-Elevation ACS Heparin and aspirin Heparin and aspirin Glycoprotein IIb/IIIa inhibitor Glycoprotein IIb/IIIa inhibitor Nitrates Nitrates  -Blocker  -Blocker Positive Markers ST Depression  1mm Dynamic ECG  or

PRISM-PLUS: Consistency of Risk Reductions The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488–1497. Age (y)  %8.5%36%  %17.8%30% Gender Female %13.4%33% Male %12.7%32% AGGRASTAT  (tirofiban HCI)Risk nHeparin+ HeparinReduction

Prognostic Value of ECG Changes: GUSTO IIb Days From Randomization Mortality, % ST-Segment Elevation and Depression ST-Segment Depression ST-Segment Elevation Isolated T-Wave Inversion Adapted from Savonitto S, et al. JAMA. 1999;281: P  0.001

Conclusion: TnI has important prognostic value for patients with unstable angina Adapted from Galvani M, et al. Circulation. 1997; 95:2053– % 27.3% P=0.02 Composite Endpoint (30 days - MI, Death) TnI- n = 69 TnI+ n = 22 Cardiac Endpoints in Unstable Angina Troponin I in CK-MB Negative Patients with ECG Changes 30

Adapted from Armstrong PW, et al. Circulation. 1998;98:1860–1868. Prognostic Value of Refractory Ischemia in Patients Without ST-Segment Elevation: GUSTO IIb Cumulative Survival 30-Day Infarction 2.6% 9.2% 25.4% % 1.00Days No Recurrent Ischemia Nonrefractory Ischemia Refractory Ischemia P<0.02

Current Limitations to the Use of GP IIb/IIIa Inhibitors Physician perceptions Physician perceptions –No incremental benefit beyond ASA-heparin –Bleeding risk is unacceptable Not sure how patients will be treated: PTCA, CABG, medical therapy Not sure how patients will be treated: PTCA, CABG, medical therapy Use of LMWH Use of LMWH Not sure whom to treat or when to treat Not sure whom to treat or when to treat

Heparin only AGGRASTAT ® (tirofiban HCl) + Heparin RR = 66% All 1570 Patients Evaluated Hours Probability of Death or MI The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488–1497. PRISM-PLUS: Combined MI and Death During Initial 48 Hours in All Patients

Thrombus (N=643) No Thrombus (N=784) % Patients With Event CompositeRefr. IschemiaMIDeathMI/Death 2% 20%* 10% 4% 12%* 6% 9%* 5%*5% Events at 30 Days * P< Adapted from Zhao XQ, et al. Circulation. 1999;100:1609–1615. Intracoronary Thrombus as a Predictor of Clinical Outcomes in Unstable Angina/NQWMI

Recent Occlusion PRISM-PLUS: Thrombus Grade Adapted from Zhao XQ, et al. Circulation. 1999;100:1609– Cumulative % Heparin (n=622) Large Recent Occlusion Tirofiban + Heparin (n=608) Possible Small Moderate Possible Small Moderate Overall Odds Ratio: 0.77 P= % 24.1% Large

TIMI Flow as a Predictor of Clinical Outcomes in UAP/NQWMI % Patients With Event 20% 12% 5% 9% Composite Refr. Ischemia MI MI/Death 6% 10% 7.4% 5.5% Events at 30 Days Adapted from Zhao XQ, et al. Circulation. 1999;100:1609–1615.

PRISM-PLUS: TIMI Flow Adapted from Zhao XQ, et al. Circulation. 1999;100:1609– Cumulative % Minimal Perfusion (TIMI 1) Heparin (n=580) Total occlusion (TIMI 0) Partial perfusion (TIMI 2) Total occlusion (TIMI 0) Partial perfusion (TIMI 2) Overall Odds Ratio: 0.65 P= % 25.5% Tirofiban + Heparin (n=570)

Acute 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 (1)-05-AGG