Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4 - ISAR-REACT 4


The goal of the trial was to evaluate treatment with unfractionated heparin/abciximab compared with bivalirudin alone among patients undergoing percutaneous coronary intervention (PCI) for non−ST-segment elevation myocardial infarction (NSTEMI).


Unfractionated heparin/abciximab will be more effective at preventing adverse events.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients between the ages of 19 and 80 years with NSTEMI undergoing PCI

    Number of enrollees: 1,721
    Duration of follow-up: 30 days
    Mean patient age: 68 years
    Percentage female: 23%
    Ejection fraction: 52%


  • Cardiogenic shock
  • Active bleeding or bleeding diathesis
  • Planned stage PCI within 30 days
  • eGFR <30 ml/min or serum creatinine >3.0 mg/dl
  • Warfarin within the past 7 days, glycoprotein IIb/IIIa inhibitor within the past 14 days, unfractionated heparin within the past 4 hours, low molecular weight heparin within the past 8 hours, and bivalirudin within the past 24 hours

Primary Endpoints:

  • Death, large recurrent MI, urgent target vessel revascularization, or major bleeding at 30 days. Large MI was defined as creatine kinase-MB >5 times upper limit of normal or new Q waves.

Secondary Endpoints:

  • Death, any MI, or urgent target vessel revascularization
  • Major bleeding defined as intracranial, intraocular, or retroperitoneal hemorrhage; a decrease in hemoglobin level >4 g/dl with overt bleeding; or the need for transfusion of 2 or more units of packed red cells
  • Stent thrombosis

Drug/Procedures Used:

Patients with NSTEMI undergoing PCI were randomized to unfractionated heparin/abciximab (n = 861) versus bivalirudin alone (n = 860).

Dosages: heparin 70 U/kg, abciximab 0.25 mg/kg bolus then 0.125 µg/kg/min for 12 hours, bivalirudin 0.75 mg/kg then 1.75 mg/kg/h for duration of PCI. All patients were given aspirin ≥325 mg and clopidogrel 600 mg prior to administration of study medications. Clopidogrel was administered for at least 6 months.

Activated clotting time was not routinely measured.

Principal Findings:

Overall, 1,721 patients were randomized. The mean age was 68 years, 23% were women, 30% had diabetes, the mean body mass index was 28 kg/m2, the mean left ventricular ejection fraction was 52%, and the median glomerular filtration rate (GFR) was 82 ml/min.

The most commonly involved artery was the left anterior descending in 37%, mean vessel diameter was 3.0 mm, mean lesion length was 18 mm, a drug-eluting stent was used in 89%, and 94% had TIMI 3 flow after PCI.

The primary outcome, death, large recurrent MI, urgent target vessel revascularization, or major bleeding occurred in 10.9% of the heparin/abciximab versus 11.0% of the bivalirudin group (p = 0.94). There was no difference according to prespecified subgroups.

Death, any MI, or urgent target vessel revascularization: 12.8% versus 13.4% (p = 0.76), respectively. Death: 1.4% versus 1.6%, large recurrent MI: 6.6% versus 7.0%, target vessel revascularization: 0.8% versus 1.3%, stroke: 0.5% versus 0.7%, major bleeding: 4.6% versus 2.6% (p = 0.02), and definite stent thrombosis: 0.6% versus 0.7%, respectively.


Among patients with NSTEMI, the use of bivalirudin alone results in similar ischemic events and less bleeding compared with unfractionated heparin/abciximab. This was a well done study, which incorporated blinded administration of study medication, strict definitions of MI and major bleeding, and contemporary dosing of unfractionated heparin. Bivalirudin appears to be the preferred antithrombin agent during PCI of NSTEMI patients pretreated with aspirin and clopidogrel. Heparin plus a glycoprotein IIb/IIIa inhibitor might still be expected to be useful for acute coronary syndrome patients undergoing PCI not pretreated with an adenosine diphosphate receptor antagonist.


Kastrati A, Neumann FJ, Schulz S, et al., on behalf of the ISAR-REACT 4 Trial Investigators. Abciximab and heparin versus bivalirudin for non−ST-elevation myocardial infarction. N Engl J Med 2011;Nov 13:[Epub ahead of print].

Presented by Dr. Adnan Kastrati at the American Heart Association Scientific Sessions, Orlando, FL, November 13, 2011.

Clinical Topics: Acute Coronary Syndromes, Anticoagulation Management, Invasive Cardiovascular Angiography and Intervention, Anticoagulation Management and ACS, Interventions and ACS

Keywords: Myocardial Infarction, Acute Coronary Syndrome, Stroke, Follow-Up Studies, Drug-Eluting Stents, Heparin, Ticlopidine, Immunoglobulin Fab Fragments, Hirudins, Purinergic P2Y Receptor Antagonists, Percutaneous Coronary Intervention, Body Mass Index, Thrombosis, Recombinant Proteins, Peptide Fragments, Stroke Volume, Glomerular Filtration Rate, Diabetes Mellitus

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