November 13th, 2011

ISAR-REACT 4: Bivalirudin Works Great, Less Bleeding

In the previously published REPLACE-2 and ACUITY trials, a trend was noted towards an increased incidence of ischemic complications with bivalirudin compared with glycoprotein IIb/IIIa treatment in high-risk patients undergoing PCI. The Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 4 (ISAR-REACT 4) trial was designed to show whether abciximab plus unfractionated heparin was superior to bivalirudin with respect to mortality, recurrent MI, urgent target-vessel revascularization, or major bleeding within 30 days.

The study enrolled 1721 NSTEMI patients undergoing PCI within 24 hrs of hospital admission. There was no significant difference between the two treatment arms with respect to the primary composite endpoint. Moreover, there was a higher rate of bleeding in abciximab and unfractionated heparin recipients


30 Day Endpoints

Abciximab + heparin

Bivalirudin (n=860)

P value

Primary Endpoint
   Death, large recurrent MI, urgent TVR* or major bleeding




Secondary Endpoints
   Death, any MI or urgent TVR*




   Major bleeding





*TVR=target vessel revascularization

In no prespecified groups, was there a suggestion of a benefit with abciximab. In this study, major bleeding was defined as the presence of intracranial, intraocular, or retroperitoneal hemorrhage; a decrease in the hemoglobin level of more than 40 g/L plus either overt bleeding or the need for transfusion of 2 or more units of packed red cells or whole blood. 

Since all patients in ISAR REACT 4 received a 600 mg loading dose of clopidogrel and most (99%) underwent PCI via the femoral approach with infrequent use of vascular closure devices (used in only 21% of patients), it isn’t known whether these results are applicable to patients who receive newer adenosine receptor antagaonists or have PCI performed through the radial artery.

Although the study was funded by Nycomed Pharma — the former distributor of bivalirudin in Europe – the company reportedly had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

This study and previous ones are consistent in showing that bivalirudin alone provides anti-ischemic protection similar to that offered by abciximab and heparin with fewer bleeding complications in patients undergoing PCI for acute NSTEMI .

So, is there any reason to use a glycoprotein IIb/IIIa rather than bivalirudin in the patient undergoing PCI? 

5 Responses to “ISAR-REACT 4: Bivalirudin Works Great, Less Bleeding”

  1. ISAR-4 raises some interesting questions. Should guidelines be amended? We had been thinking that bivalirudin should be reserved for patients with a higher risk of bleeding – is that no longer necessary?

  2. Pietro Vandoni, Medical Doctor, says:

    After a first look to ISAR REACT 4 results I think I will not change my actual choice: UFH or LMWH in ACS patients treated with DAPT (600 mg load of clopidogrel or parasugrel) and standard risk of bleeding and bivalirudin if the estimated risk of bleeding is high.
    Abcximab only for bail-out cases and never upstream as the recent guidelines recommend. Where does the need to change guidelines come from? Maybe I missed something. Thank you

    Competing interests pertaining specifically to this post, comment, or both:

  3. Elliott Antman, the program director for the AHA scientific sessions and an author of the ACS guidelines, provided this comment for CardioExchange:

    “In an ACS patient we need to provide both anti platelet and anticoagulant therapy.In an era when we did not have powerful P2Y12 inhibitors there was a more compelling argument to use an intravenous GPIIb/IIIa inhibitor. Now with drugs like clopidogrel or the second generation P2Y12 inhibitors in such common use, the case for drugs like abciximab is less compelling. Having a rapid onset and offset anticoagulant like bivalirudin is attractive for management of the NSTEACS patient”

  4. Douglas Trenkle, BS,DO says:

    That may well be. But as the evidence has accumulated with GIIbIIIa medications, RRR is consistent up to 6 months in morbidity and mortality with and without clopidogrel. And in fact PURSUIT showed that the highest inhospital mortality was in those who recieved PCI, and the lowest in those with GIIbIIIa alone without PCI.

  5. Im still struggling with the fact that the ischemic outcomes are unchanged from ISAR-REACT-3 to ISAR-REACT-4. I find it amazing that bivalirudin did as well heparin in ISAR-REACT-3, and that adding a potent agent like abciximab didnt add any oomph against bivalirudin. That the bleeding outcomes did’nt separate out even further significantly also seems troublesome to me. This is abciximab we are talking about-this stuff causes alveolar hemorrhage!!

    Competing interests pertaining specifically to this post, comment, or both:
    None relevant to the above comment.