Percutaneous coronary interventions, mostly with implantation of bare-metal or drug-eluting stents, are commonly used to treat patients with coronary artery disease. Various periprocedural adjunct antithrombotic therapies have been investigated and are being used. Unfractionated heparin (UFH) has been the standard adjunctive antithrombin therapy during PCI for more than 25 years. Combined antiplatelet treatment consisting of aspirin and a thienopyridine has significantly reduced early ischaemic events following coronary stenting (1). Thienopyridines act by irreversibly inhibiting the platelet adenosine diphosphate (ADP) P2Y12 receptor. Compared to ticlopidine, clopidogrel has the advantage of a more favourable side effect profile (2) and more rapid onset of action.(3,4) Pretreatment with a loading dose of 300mg clopidogrel improved outcomes (5-7) and is recommended by current guidelines for patients undergoing PCI. (8) More recently, trials have shown that the larger loading dose of 600mg achieves more rapid and more potent inhibition of platelet aggregation than 300 mg do.(9-11) The results of several randomized controlled trials suggest that pretreatment with 600mg clopidogrel might obviate the need for IIb/IIIa inhibitors in a broad spectrum of patients undergoing PCI (12-14) although no formal direct comparison of different clopidogrel doses has been assessed by trials sufficiently powered for clinical endpoints. The Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) trial showed that after pretreatment with 600mg clopidogrel for at least 2 hours before the intervention, additional use of abciximab was not associated with any clinically measurable benefit among low-to-intermediate risk patients who underwent PCI.(12) Even in higher risk settings such as small vessel size (14) and the presence of diabetes (13)additional use of abciximab was not associated with a measurable clinical benefit in patients pretreated with 600mg clopidogrel. An important exception is the group of patients with non-ST-segment elevation ACS. In the ISAR-REACT-2 trial that enrolled this category of patients those with an elevated troponin level did benefit from abciximab even after pretreatment with 600mg clopidogrel.(15) The recently completed ISAR-REACT-3 trial compared unfractionated heparin with the direct thrombin inhibitor bivalirudin in biomarker negative patients with stable and unstable angina undergoing contemporary PCI. Bivalirudin did not provide "net clinical benefit" - did not reduce the quadruple endpoint - at 30 days compared to unfractionated heparin. However, there was a significant reduction in bleeding with bivalirudin (16) The heparin dose regimen used in ISAR-REACT-3 diverges from current US practice insofar as the majority of patients received a bolus dose of 140 U/kg with no follow up ACT measurement and no additional heparin doses. Although heparin has been the standard antithrombin therapy in interventional cardiology for decades, its optimal dose is still not known. During the last years there has been a trend towards using lower heparin doses. In most interventional trials in the United States it is now current practice to use a bolus of not more than 100 U/kg. (8) Many interventionalists believe that a dose lower than 140 U/kg is associated with a better clinical outcome. However, no studies have been performed to identify the most appropriate dose of heparin. Since pretreatment with clopidogrel has proven to reduce ischemic events, a heparin dose of 140U/kg might conceivably be too high. A lower dose might prove to be as effective in preventing ischemic endpoints while reducing the risk of bleeding if patients were pretreated with 600mg clopidogrel prior to the intervention. Therefore the aim of this trial is to evaluate whether a reduction in the heparin dose from 140 to 100 U/kg is associated with a better net clinical outcome in patients undergoing PCI after pretreatment with 600mg clopidogrel. The hypothesis to be tested is whether a reduced dose of 100U/kg heparin is superior to the higher dose of 140U/kg used in the ISAR-REACT-3 trial (historical control) regarding the combined incidence of death, myocardial infarction, urgent target vessel revascularization within 30 days and in hospital major bleeding. The ISAR-REACT-3a trial will enroll a patient population with a similar risk profile to that of patients included in ISAR-REACT-3. Biomarker negative patients with stable or unstable angina undergoing PCI will receive a reduced dose heparin bolus of 100U/kg. Results will be compared with the ISAR-REACT-3 trial (historical control). Primary comparison will be with the heparin arm of ISAR-REACT-3 regarding the primary endpoint ("Net clinical benefit", the combined incidence of death, myocardial infarction, urgent target vessel revascularization within 30 days and in hospital major bleeding). A secondary aspect will be the comparison with the historical bivalirudin group of the ISAR-REACT-3 trial.