REPLACE-2: The Randomized Evaluation of PCI Linking ANGIOMAX to Reduced Clinical Events ^1,2

• Summary|
• Trial Design|
• Clinical Outcomes

Summary

One of the largest double-blind, randomized contemporary trial of patients undergoing PCI comparing Angiomax^® (bivalirudin) with provisional glycoprotein (GP) IIb/IIIa inhibitor to heparin + planned GP IIb/IIIa demonstrated:¹

• Documented efficacy in suppressing ischemic events at 30 days (7.6% vs 7.1%; P = .40) ¹
• Major bleeding^† with ANGIOMAX with "provisional" GP IIb/IIIa inhibitor vs heparin + GP IIb/IIIa inhibitor was reduced by 41% (2.4% vs 4.1%, respectively, P < .001)¹
• Acute coronary syndrome (ACS)^‡ was present in 22% of patients (n=1,330) in REPLACE-2 undergoing
  PCI ¹
• At 1 year, mortality rates in the ANGIOMAX + "provisional" GP IIb/IIIa inhibitor and heparin + GP IIb/IIIa inhibitor groups were 1.9% and 2.5% (P = .16), respectively.²
• Reduced procedural costs ($335/patient) and total resource in-hospital costs ($405/patient) and 30-day follow-up costs ($374/patient) were seen in the REPLACE-2 economic subanalysis³

† Please see important safety information and bleeding definitions. ‡ ACS was defined in REPLACE-2 as unstable angina within preceding 48 hours or MI within the prior 7 days.1

Trial Design

REPLACE-2: Compared ANGIOMAX with "provisional" GP IIb/IIIa to heparin + planned GP IIb/IIIa in a double-blind, double-dummy, randomized, controlled trial of 6002 patients undergoing urgent or elective PCI.

REPLACE-2 Trial Design

This study was designed to demonstrate that use of ANGIOMAX as the foundation anticoagulant permits provisional use of GP IIb/IIIa and provides clinical outcomes (rates of ischemic and hemorrhagic events) that are as effective as the current standard of low-dose weight-adjusted heparin + GP IIb/IIIa.

Clinical End Points: The primary end point was a composite of 30-day death, MI, urgent revascularization, or in-hospital major hemorrhage. Key secondary end points include the composite incidence of death, MI, or urgent revascularization at 30 days, as well as the composite incidence of death, MI, or target vessel revascularization assessed at 6 months, and 1-year mortality rates.

Safety end points consist of major hemorrhage, defined as the occurrence of intracranial bleeding, retroperitoneal bleeding, or overt bleeding with a decrease in hemoglobin of >3 g/dL or leading to a transfusion of ≥2 units of blood, or a drop in hemoglobin >4 g/dL with no observed bleeding.

Patient Characteristics and Risk Factors

Adapted from Lincoff, et al, JAMA, 2003.

Documented efficacy vs heparin + GP IIb/IIIa inhibitor in suppressing ischemic events in REPLACE-2¹

• REPLACE-2 was one of the largest clinical trials conducted to evaluate antithrombotics in PCI
  (N=6,002)¹

• Major bleeding^† with ANGIOMAX with "provisional" GP IIb/IIIa inhibitor vs heparin + GP IIb/IIIa inhibitor was 2.4% vs 4.1%, respectively (P<.001)
• Acute coronary syndromes (ACS)^‡ was present in 22% of patients (n=1,330) in REPLACE-2 undergoing PCI

* In REPLACE-2: 93% of ANGIOMAX patients received ANGIOMAX monotherapy.1 ‡ ACS was defined in REPLACE-2 as unstable angina within preceding 48 hours or MI within the prior 7 days.1 † Please see important safety information and bleeding definitions.

REPLACE-2 mortality rates at 1 year confirm long-term efficacy²

• In REPLACE-2, postprocedural bleeding was more strongly correlated with 1-year mortality than was creatine kinase MB elevation²

* In REPLACE-2, 93% of ANGIOMAX patients received ANGIOMAX monotherapy.1 § Mortality rates based on 1-year Kaplan-Meier estimates.2

Proven Efficacy in Broad Cross Section of High-Risk Patient Characteristics

• Patients enrolled in REPLACE-2 represented a broad cross section of high-risk patient characteristics similar to that seen in ESPRIT⁴ and EPISTENT⁵
• Baseline characteristics were similar between treatment groups with the exception of having more diabetic patients in the ANGIOMAX with provisional GP IIb/IIIa treatment group
• The provisional use rate of GP IIb/IIIa for the ANGIOMAX and heparin groups were 7.2% and 5.2%, respectively
• Thienopyridines were used in approximately 86% of ANGIOMAX with provisional GP IIb/IIIa patients and 85% of patients receiving heparin + GP IIb/IIIa
• Patients undergoing either elective or urgent PCI were evenly matched between the 2 treatment groups

One-Year Mortality Consistent in All Prespecified Subgroups

Mortality differences durable and consistent among all subgroups through 1 year

* 93% of ANGIOMAX patients received ANGIOMAX monotherapy. Only 7.2% of ANGIOMAX patients received "provisional" GP IIb/IIIa.6 † Defined as angina within 48 hours or MI within 7 days. ‡ Pretreatment within prior 48 hours.