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ISAR REACT 3A: A trial of reduced dose of unfractionated heparin in patients undergoing percutaneous coronary interventions

Acute Coronary Syndromes

Schulz Stefanie, MD
Presenter | see Discussant report | read press release Webcasts become available 24h after the presentation
Schulz, Stefanie
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List of Authors:

Stefanie Schulz, MD; Julinda Mehilli, MD; Franz-Josef Neumann, MD; Tibor Schuster, PhD; Steffen Massberg, MD; Christian Valina, MD; Melchior Seyfarth, MD; Jürgen Pache, MD; Karl-Ludwig Laugwitz, MD; Hans-Joachim Büttner, MD; Gjin Ndrepepa, MD, Albert Schömig, MD; Adnan Kastrati, MD; for the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3A Trial Investigators


Aims: Although a 140 U/kg dose of unfractionated heparin (UFH) was comparable to bivalirudin in terms of net clinical outcome in the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment (ISAR-REACT) 3 trial, it was associated with a higher risk of bleeding. We designed this study to assess whether a reduction in the UFH dose from 140 to 100 U/kg is associated with improved net clinical outcome.

Methods and Results: A total of 2,505 biomarker negative patients undergoing percutaneous coronary intervention (PCI) after clopidogrel pretreatment received a single bolus of 100 U/kg UFH. The primary endpoint was net clinical outcome − a quadruple endpoint of death, myocardial infarction, urgent target-vessel revascularization within 30 days, or in-hospital REPLACE 2 defined major bleeding. The primary comparison was with the historical UFH group of ISAR-REACT 3 (2,281 patients). In a second analysis we checked for non-inferiority against the historical bivalirudin arm of ISAR-REACT 3 (2,289 patients). The incidence of the primary endpoint was 7.3% in the lower UFH dose group as compared with 8.7% in the higher UFH dose group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.67-1.00; P=0.045). The incidence of major bleeding was 3.6% in the lower UFH dose group and 4.6% in the higher UFH dose group (HR, 0.79; 95% CI, 0.59-1.05; P=0.11). The lower UFH dose met the criterion of non-inferiority compared to bivalirudin (P<0.001).

Conclusion: In biomarker negative patients undergoing PCI after clopidogrel loading, a reduced dose of 100 U/kg UFH provided net clinical benefit compared to the historical control of 140 U/kg UFH in the ISAR-REACT 3 trial. The benefit was mostly driven by reduction in bleeding.

Christian Hamm, FESC
Discussant | see Presenter abstract Webcasts become available 24h after the presentation
Hamm, Christian
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Since the first days of percutaneous coronary interventions (PCI) it has been a common understanding to treat patients with a combination of antiplatelet and anticoagulant drugs to prevent thrombotic complications.(1) Numerous anticoagulants have been tested during elective PCI.(2) Nonetheless aspirin and unfractionated heparin (UFH) have survived more than 30 years as the standard regimen, particularly in patients with stable angina. After the introduction of stents, the antiplatelet regimen was supplemented by thienopyridines. The administration of glycoprotein IIb/IIIa antagonists did not render additional benefits in the setting of elective interventions.(3) Bivalirudin as a direct antithrombin was shown to be safer and effective in patients with acute coronary syndromes.(4, 5) However, the anticoagulation management during elective procedures gained only limited attention. Tradition and habits may influence the selection of anticoagulants and especially the dose of heparin.(6) This is even more surprising, since PCI technique and material improved considerably and bleeding complications moved in our focus. Much of the data regarding heparin administration during PCI were obtained before introduction of coronary stenting and potent antiplatelet agents.
Was there no need to address this question or why was there no lobby?

... Full Text published as Hot Line Commentary in Euro Heart Journal (doi )


1. Gruntzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979; 301(2):61-68.

2. Neuhaus KL, Zeymer U. Prevention and management of thrombotic complications during coronary interventions. Combination therapy with antithrombins, antiplatelets, and/or thrombolytics: risks and benefits. Eur Heart J 1995; 16 Suppl L:63-67.

3. Claeys MJ, Van der Planken MG, Bosmans JM, Michiels JJ, Vertessen F, Van Der Goten P, Wuyts FL, Vrints CJ. Does pre-treatment with aspirin and loading dose clopidogrel obviate the need for glycoprotein IIb/IIIa antagonists during elective coronary stenting? A focus on peri-procedural myonecrosis. Eur Heart J 2005; 26(6):567-575.

4. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358(21):2218-2230.

5. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355(21):2203- 2216.

6. Swanson N, Hogrefe K, Stephens Lloyd A, Gershlick A. Current perspectives on British use of adjunctive therapies during coronary interventions. Int J Cardiol 2001; 79(2- 3):119-125; discussion 126-117.


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Hot Line II - Coronary artery disease
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.