Lincoff AM Bittl JA Harrington RA et al for the Replace2 Investigators Reference

JAMA 2003; 289: 853-863 Abstract

CONTEXT: The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI). OBJECTIVE: To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (GP IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned GP IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications. DESIGN, SETTING, AND PARTICIPANTS: The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 601 0 patients undergoing urgent or elective PCI at 233 community and referral hospitals in 9 countries from October 2001 through August 2002. INTERVENTIONS: Patients were randomly assigned to receive intravenous bivalirudin (0.75mg/kg bolus plus 1.75mg/kg per hour for the duration of PCI), with provisional GP IIb/IIIa inhibition (n = 2999), or heparin (65 U/kg bolus) with planned GP IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI. MAIN OUTCOME MEASURES: The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization. RESULTS: Provisional GP IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs. 10% of patients in the heparin-plus-GP IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; p = 0.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs. 7.1% of patients in the heparin-plus-GP IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; p = 0.40). Prespecified statistical criteria for non-inferiority to heparin plus GP IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs. 4.1%; p < 0.001). CONCLUSIONS: Bivalirudin with provisional GP IIb/IIIa blockade is statistically not inferior to heparin plus planned GP IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.


In balloon angioplasty trials, bivalirudin was shown to have a favourable profile relative to heparin as a substitute anti-thrombin. The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE) 2 was designed to test two hypotheses in contemporary stent percutaneous coronary intervention (PCI): (1) that bivalirudin would prove superior to heparin in historical controls, and (2) that bivalirudin (with "bailout" use of a glycoprotein IIb/IIIa (GP IIb/IIIa) blocker) would be non-inferior to a combination of unfractionated heparin and a GP IIb/IIIa inhibitor.

Patients undergoing PCI were randomized to the bivalirudin with bailout GP IIb/IIIa inhibitor therapy or heparin with planned GP IIb/IIIa inhibitor therapy. Only 7% of patients in the bivalirudin group received "bailout" GP IIb/IIIa inhibitor. All patients received aspirin and 85% were pre-treated with a thienopyridine. At 30 days, death, myocardial infarction (MI), urgent revascular-ization, and major bleeding events were tabulated.

There was less bleeding in the bivalirudin arm. Furthermore, bivalirudin was found to be noninferior to unfractionated heparin plus planned GP IIb/IIIa blockade during PCI.

Citation Count 106

Related References

1. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor.

Circulation 1998; 97: 251-256.

2. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. N Engl J Med 1995; 333: 764-769.

3. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ, for the Bivalirudin Angioplasty Study Investigators. Bivalirudin vx heparin during coronary angioplasty for unstable or post-infarction angina: final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J 2001; 142: 952-959.

4. Antman EM. Should bivalirudin replace heparin during percutaneous coronary interventions? JAMA 2003; 289: 903-905.

Key message

The direct thrombin inhibitor bivalirudin is a superior replacement to unfractionated heparin as an adjunct to PCI. Bleeding (both major and minor) is less common with bivalirudin, which makes bivalirudin particularly attractive in PCI patients who are at a high risk for bleeding. The strategy of bivalirudin with "bailout" GP IIb/IIIa inhibitor is non-inferior to the combination of unfractionated heparin plus a GP IIb/IIIa inhibitor in low-to-intermediate risk PCI patients, with the advantage of bivalirudin being imparted with reduced rates of bleeding (but not with improvements in efficacy).

Why it's important

Fundamentally, heparin is not a particularly good anti-thrombin. Also, despite their efficacy, the high cost of GP IIb/IIIa inhibitors and the risk of increased bleeding have limited their widespread use to approximately 50-60% of patients undergoing PCI. The REPLACE-2 trial established bivalirudin as an excellent replacement for heparin during PCI. In lower-risk patients, substitution of bivalirudin for GP IIb/IIIa inhibitors would result in lower rates of bleeding along with cost savings without compromising efficacy. Notably, bivalirudin has not been proven in higher-risk patients, including acute coronary syndrome patients and ST-elevation MI. Nonetheless, bivalirudin is an obvious choice for a PCI patient with heparin-induced thrombocytopenia or who is at high risk for bleeding complications.


The REPLACE-2 trial was a well-designed, randomized, non-inferiority trial which established a role for the direct thrombin inhibitor bivalirudin in PCI.


Managing anticoagulation therapy in the pre-PCI hospital phase (where bivalirudin has not been established) with the subsequent use of bivalirudin in the catheterization lab is confusing at best, and was not evaluated in REPLACE-2. Patients enrolled in REPLACE-2 were in lower-risk categories, making the generalizability of the findings less certain. The criteria for non-inferiority was only marginally achieved. Whether additional benefit could be achieved with the combination of bivalirudin plus a GP IIb/IIIa inhibitor is not known.


The REPLACE-2 trial has resulted in substantial replacement of heparin alone, as well as heparin with a GP IIb/IIIa antagonist, in routine PCI. That unfractionated heparin, the standard of care in PCI for more than 25 years, will ultimately be replaced is not in question. Nonetheless, while bivalirudin is an attractive anticoagulant, additional data needs to be accrued before we will be able to identify the optimal anti-platelet and anti-thrombin cocktail that provides the safest, most efficacious, and most cost-effective approach for the entire spectrum of patients undergoing PCI.

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