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


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


Characteristic
ANGIOMAX with
"provisional"
GP IIb/IIIa
(N = 2994)
Heparin +
GP IIb/IIIa
(N = 3008)
Age (y)
62.6 + 10.8
62.6 + 11.0
Gender (%F)
25.3
25.9
Diabetes (%)
28.1
26.1
HTN (%)
66.0
68.0
Tobacco prior y (%)
27.2
26.0
Prior MI (%)
37.4
36.7
Prior PCI (%)
34.5
35.3
Prior CABG (%)
18.0
18.8
Hx CVA (%)
2.5
2.2
Hx of CHF (%)
7.3
6.6

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.

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.

1Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-863.

2Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA. 2004;292:696-703.

3Cohen DJ. Economic implications of the use of direct thrombin inhibitors in percutaneous coronary intervention. Adv Stud Pharm. 2005;2:80-89.

4ESPRIT Investigators. Novel dosing regimen of eptifibatide in planned coronary stent implementation (ESPRIT): a randomised, placebo-controlled trial. Lancet 2000;356:2037-2044. Erratum in:Lancet 2001;357:1370.

5EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. The EPISTENT Investigators. Evaluation of platelet IIb/IIIa inhibitor for stenting. Lancet. 1998;352:87-92.

6Lincoff AM, Bittl JA, Harrington RA, et al; for the REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853-63. Erratum in: JAMA. 2003;289:1638.