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

• Summary
• Trial Design
• Clinical Outcomes

Summary

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

• Proven efficacy in preventing ischemic events at 30 days (7.6% vs 7.1%; P = .40)
• Significant 41% reduction in in-hospital major bleeding (4.1% vs 2.4%; P < .001)
• Mortality results favoring ANGIOMAX at 1 year confirmed in high-risk patients.

Trial Design

REPLACE-2: Compared ANGIOMAX with “provisional” GP IIb/IIIa to heparin plus 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 plus 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

Clinical Outcomes

REPLACE-2 30-day Outcomes

* 93% of ANGIOMAX patients received ANGIOMAX monotherapy. Only 7.2% of ANGIOMAX patients received ”provisional” GP IIb/IIIa.
† Myocardial infarction was defined by new significant Q-waves in 2 or more contiguous electrocardiographic leads or elevation in creatine kinase (CK) or its MB isoenzyme (obtained in all patients every 8 hours for the 24 hours post-procedure) to >3 times the upper limit of local normal within 2 days of revascularization or to >2 times the upper limit of normal outside of the setting of revascularization.
‡ Defined as: intracranial or retroperitoneal bleeding; transfusion of 2 or more units of blood/blood products; a fall in hemoglobin of >4 g/dL, whether or not bleeding was identified; clinically overt blood loss (spontaneous or nonspontaneous) with a fall in hemoglobin of >3 g/dL^1,3.

One-Year Cumulative Mortality—Absolute Difference Widens From 0.2% at 30 Days to 0.6% at 1 Year

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 plus 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.^1
†Defined as angina within 48 hours or MI within 7 days.
‡ Pretreatment within prior 48 hours.

Safety

ANGIOMAX with “provisional” GP IIb/IIIa treatment significantly reduced the risk of bleeding

• ANGIOMAX with “provisional” GP IIb/IIIa reduced major bleeding by 41% compared to patients receiving heparin plus GP IIb/IIIa (2.4% vs 4.1%; P <.001)

Bleeding Outcomes

* Defined as: intracranial or retroperitoneal bleeding; transfusion of 2 or more units of blood/blood products; a fall in hemoglobin of >4 g/dL, whether or not bleeding was identified; clinically overt blood loss (spontaneous or nonspontaneous) with a fall in hemoglobin of >3 g/dL^1,3

• Patients treated with ANGIOMAX exhibited significantly lower rates of major hemorrhage, minor hemorrhage, thrombocytopenia, access-site bleeding, and major organ bleeds and lower requirements for blood transfusions than patients receiving heparin plus GP IIb/IIIa
• Overt hemorrhage from the arterial access site was the most frequent underlying cause of major hemorrhage
• Retroperitoneal hemorrhage also occurred more frequently in association with heparin treatment than with ANGIOMAX treatment. There were few intracranial hemorrhages in either randomized group

Bleeding a Predictor of Mortality

Patients who experience a major hemorrhage are more likely to die within 30 days

In REPLACE-2, patients who had a major hemorrhage were 30 times more likely to die within 30 days than those who did not have a major bleeding complication (10/195 [5.2%] vs 9/5007 [0.2%], P <.001).^6,7 Multivariate analysis identified major hemorrhage as the third strongest predictor of 1-year mortality (OR, 3.53; 95% CI 1.91-6.53,
P <.0001) after renal function and congestive heart failure.⁶

Impact of In-Hospital Major Bleeding on Early and Late Mortality in REPLACE-2 (pooled analysis)

Adapted from Stone GW. Advantages of direct thrombin inhibition in high and low risk patients. J Invasive Cardiol. 2004;16(Suppl. G):12G-17G.

Treatment With Heparin Is the Most Important Risk Factor for Bleeding

• Based on data from a multivariate logistic regression analysis, treatment with heparin plus GP IIb/IIIa is the most important risk variable for major hemorrhage after accounting for the independent effects of all other covariables
• These data further support the conclusion that ANGIOMAX with or without “provisional” GP IIb/IIIa has a better safety profile than heparin or heparin plus GP IIb/IIIa at similar or superior levels of anticoagulant effect
• The multivariate logistic regression model was developed to identify patient and treatment variables that were able to predict the risk of major hemorrhage in association with treatment. A comprehensive list of potential risk variables was considered, which included almost all candidate predictors of major hemorrhage cited in the literature. Among the risk variables, randomization to treatment with heparin plus GP IIb/IIIa was one of the most important independent predictors of risk of major hemorrhage (odds ratio 1.8;
  P<.0002).^6-7 Other independent covariables predicting risk of major hemorrhage were:
  • Creatinine clearance
  • Age >75 years
  • Female gender
  • LMWH treatment in prior 48 hours

The intensity of anticoagulation as measured by ACT levels was not found to be predictive of risk of major hemorrhage in any univariate or multivariate analysis performed. These data are consistent with published reports that have shown age, female gender, and renal function to be important predictors of risk of hemorrhage in PCI.

Both Major and Minor Bleeding Events Increase the Risk of Mortality in PCI

• In a retrospective analysis of 10,974 patients undergoing PCI from 1991-2000, Kinnaird et al reported TIMI major bleeding as an independent risk factor for in-hospital mortality (OR 3.5; 95% CI 1.9-6.7; P = .0001)⁸
• Patients who experienced major bleeding had significantly (P <.001) higher rates of death (7.5% vs. 0.6%), Q-wave MI (1.2% vs. 0.2%), non–Q-wave MI (30.7% vs 11.8%) and repeat lesion revascularization (1.9% vs 0.3%) compared to patients with no bleeding complications
• Even TIMI minor bleeding significantly increased the risk of death vs patients without bleeding (1.8% vs 0.6%, P <.001)
• At 1 year, mortality rates were 17.2%, 9.1% and 5.5% for patients with major, minor and no bleeding, respectively

Safety Considerations

ANGIOMAX with provisional use of glycoprotein IIb/IIIa inhibitor is indicated for use as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI), and in patients with or at risk for heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. ANGIOMAX is intended for use with aspirin and has been studied only in patients receiving concomitant aspirin. ANGIOMAX is contraindicated in patients with active major bleeding or hypersensitivity to ANGIOMAX or its components. The most common (10%) adverse events for ANGIOMAX were back pain, pain, nausea, headache, and hypotension. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of ANGIOMAX administration. Please see complete prescribing information.