Optimal treatment of STEMI relies on early mechanical reperfusion with PPCI [1]. Successful revascularisation requires effective adjunctive pharmacology, ideally with agents that provide rapid and reliable anti-platelet and anti-thrombotic effects. A delicate balance exists between effective inhibition of thrombosis and treatment-related bleeding. Incomplete suppression of platelet and thrombin activity may result in stent thrombosis. Advances in anti-thrombotic pharmacology have facilitated a reduction in bleeding risk. The HORIZONS-AMI randomised controlled trial compared bivalirudin with heparin plus GPIIb/IIIa antagonists. In both groups aspirin and the P2Y12 inhibitor clopidogrel were administered. The trial demonstrated a reduced rate of net clinical events and major bleeding with bivalirudin over the previous gold standard treatment with unfractionated heparin and GPIIb/IIIa antagonists [2]. Additionally bivalirudin demonstrated a reduced 30 day mortality. Despite the overall superiority of bivalirudin, an excess of acute stent thromboses (with the majority of events occurring within 5 h of the PCI) was observed in the bivalirudin (2.6%) compared to the heparin+GPIIb/IIIa group (0.9%). Interestingly, the lack of pre-randomization heparin was one of the independent predictors of acute stent thrombosis [3]. Bivalirudin reversibly binds to thrombin, and has a half-life of 25 min. Upon cessation of the infusion, plasma levels rapidly fall to below that demonstrated to reduce ischemic events in PCI. In a highly prothrombotic setting such as STEMI, it may be important to assure peri-procedural thrombin inhibition with an extended infusion. Variabilityof response to clopidogrel andconcerns regardingspeedof onset of ADP-receptor inhibition has led to the adoption of newer generation P2Y12 inhibitors with faster onset of action, greater consistency of effect and increased platelet inhibition. Prasugrel, an irreversible P2Y12-receptor inhibitor demonstrates improved clinical outcomes compared to clopidogrel [4–6]. It has been speculated that combining prasugrel with bivalirudin may negate the risk of early stent thrombosis observed in HORIZONS-AMI through more rapid and consistent platelet inhibition. However, the trial testing this hypothesis (BRAVE-4 trial, ClinTrial.gov NCT00976092) will not publish results before 2013.