Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment - ISAR-REACT 3


The goal of this trial was to assess whether bivalirudin is superior to unfractionated heparin (UFH) in terms of ischemic and hemorrhagic endpoints in troponin-negative patients undergoing percutaneous coronary intervention (PCI), after pretreatment with clopidogrel.


Bivalirudin would be superior to UFH as an adjunct anticoagulant in troponin-negative patients undergoing PCI.

Study Design

Study Design:

Patients Enrolled: 4,570
Mean Follow Up: 1 year
Mean Patient Age: 67
Female: 24
Mean Ejection Fraction: 58%

Patient Populations:

  • Biomarker-negative (troponin T <0.03 μg/L or CK-MB less than ULN) patients undergoing PCI
  • Received 600 mg of clopidogrel at least 2 hours prior to the procedure
  • Age >18 years


  • Acute coronary syndromes with positive biomarkers or ST-elevation MI <48 hours
  • Cardiogenic shock
  • History of heparin-induced thrombocytopenia or other bleeding diatheses
  • Creatinine >3 mg/dl

Primary Endpoints:

  • Composite rate of death, MI (creatine kinase-myocardial band [CK-MB] >2x upper limit of normal [ULN]), urgent TVR within 30 days, or in-hospital major bleeding

Secondary Endpoints:

  • Composite rate of death, MI (CK-MB >2x ULN), or urgent TVR

Drug/Procedures Used:

Patients who were biomarker negative, and who were undergoing PCI for stable or unstable angina were randomized to receive either UFH (bolus of 140 U/kg, followed by placebo infusion) or bivalirudin (bolus of 0.75 mg/kg, followed by infusion of 1.75 mg/kg/hr) during the procedure, in addition to 600 mg of clopidogrel and ≥325 mg aspirin at least 2 hours prior to the procedure.

Concomitant Medications:

All patients received aspirin 80-325 mg indefinitely. Clopidogrel was continued as 75-150 mg/day for ≤3 days, and then 75 mg/day for at least 1 month after balloon angioplasty or implantation of bare-metal stents and for at least 6 months after implantation of drug-eluting stents.

Principal Findings:

A total of 4,570 patients were randomized, 2,289 to the bivalirudin arm, and 2,281 to the UFH arm. The baseline characteristics of the two arms were comparable. About 27.4% of the patients were diabetic. The majority of patients (81.7%) had stable angina; the rest had unstable angina. The baseline ejection fraction was 58%, and 80% had evidence of multivessel disease. The majority of stents (87.7%) were drug-eluting stents.

The primary endpoint, a composite rate of death, myocardial infarction (MI), urgent target vessel revascularization, or in-hospital major bleeding at 30 days, was similar between the two arms (8.3% vs. 8.7% for bivalirudin and UFH, respectively; relative risk [RR] 0.94, 95% confidence interval [CI] 0.77-1.15; p = 0.57). The incidence of death, MI, and urgent target vessel revascularization (TVR) was 0.1% and 0.2% (p = 0.7), 5.6% and 4.8% (p = 0.24), and 0.8% and 0.7% (p = 0.75), for bivalirudin and UFH, respectively. The secondary endpoint of death, MI, and urgent revascularization at 30 days was 5.9% in the bivalirudin arm and 5.0% in the UFH arm (RR 1.16, 95% CI 0.91-1.49; p = 0.23).

The incidence of major bleeding was significantly reduced by 33% with bivalirudin (3.1%) compared with UFH (4.6%) (RR 0.66, 95% CI 0.49-0.90; p = 0.008). Similarly, the incidence of minor bleeding was significantly reduced (p = 0.0001). The incidence of transfusions and thrombocytopenia was similar between the two groups at 30 days.

At 1 year, the incidence of the primary endpoint was similar between the bivalirudin and heparin arms (17.1% vs. 17.5%, p = 0.82). Other endpoints such as death (1.9% vs. 1.7%, p = 0.67), MI (6.0% vs. 5.3%, p = 0.32), TVR (11.2% vs. 12.5%, p = 0.18), and definite stent thrombosis (0.7% vs. 0.7%, p = 1.0) were also similar between the two arms.


Bivalirudin had outperformed UFH (without glycoprotein IIb/IIIa) in a few trials, but pretreatment with clopidogrel was not routinely accomplished in these trials. This randomized trial sought to define the optimal adjunct anticoagulation therapy for troponin-negative patients with stable and unstable angina undergoing PCI, who were pretreated with 600 mg of clopidogrel. The results of this trial indicate that bivalirudin is not superior to UFH in these patients in reducing the incidence of death, MI, or need for urgent revascularization, although the incidence of major and minor bleeding is significantly reduced at 30 days. No difference was noted in any of the ischemic endpoints up to 1 year of follow-up.

The dose of heparin used in this study (140 U/kg) is higher than the dose used in other recent PCI trials. Moreover, activated clotting time was not routinely monitored in these patients. It is unknown to what extent this may have affected the primary endpoint, especially bleeding.


Schulz S, Mehilli J, Ndrepepa G, et al., on behalf of the ISAR-REACT 3 Trial Investigators. Bivalirudin vs. unfractionated heparin during percutaneous coronary interventions in patients with stable and unstable angina pectoris: 1-year results of the ISAR-REACT 3 trial. Eur Heart J 2010;Feb 11:[Epub ahead of print].

Kastrati A, Neumann FJ, Mehilli J, et al., on behalf of the ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688-96.

A Randomized, Double-Blind, Active-Controlled, Multi-Center Trial (ISAR-REACT 3) of Bivalirudin Versus Unfractionated Heparin in Troponin-Negative Patients Undergoing Percutaneous Coronary Interventions After Pre-Treatment With 600 mg of Clopidogrel. Presented by Dr. Adnan Kastrati at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Clinical Topics: Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Stable Ischemic Heart Disease, Chronic Angina

Keywords: Risk, Myocardial Infarction, Follow-Up Studies, Platelet Aggregation Inhibitors, Angina, Stable, Drug-Eluting Stents, Heparin, Troponin T, Ticlopidine, Hirudins, Percutaneous Coronary Intervention, Biological Markers, Thrombosis, Recombinant Proteins, Peptide Fragments, Confidence Intervals, Diabetes Mellitus, Thrombocytopenia

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