Series www.thelancet.com Vol 382 August 17, 2013 633 ST-segment Elevation Myocardial Infarction 2 What is the optimum adjunctive reperfusion strategy for primary percutaneous coronary intervention? Nicholas Curzen, Paul A Gurbel, Aung Myat, Deepak L Bhatt, Simon R Redwood Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event. As understanding of its pathophysiology has improved, the central role of platelets in initiation and orchestration of this process has become clear. Key components of STEMI include formation of occlusive thrombus, mediation and ultimately amplification of the local vascular inflammatory response resulting in increased vasoreactivity, oedema formation, and microvascular obstruction. Activation, degranulation, and aggregation of platelets are the platforms from which these components develop. Therefore, prompt, potent, and predictable antithrombotic therapy is needed to optimise clinical outcomes after primary percutaneous coronary intervention. We review present pharmacological and mechanical adjunctive therapies for reperfusion and ask what is the optimum combination when primary percutaneous coronary intervention is used as the mode of revascularisation in patients with STEMI. Introduction Acute ST-segment elevation myocardial infarction (STEMI) is a dynamic, thrombus-driven event in which platelets have a central role (igure 1). Antithrombotic therapy optimises clinical outcomes for patients after primary percutaneous coronary intervention (PCI). Contemporary European and US guidelines for treat- ment of STEMI have assigned a class IA recom- mendation for primary PCI as the reperfusion strategy of choice when done by an experienced team within 90 min of irst medical contact. 1,2 However, various preprocedural and periprocedural pharmacotherapeutic options are available to combat the prothrombotic milieu that exists both as a direct sequel of the vaso-occlusive process allied to the vessel trauma, and distal embolisation caused by mechanical revascularisation. In this Series paper we focus solely on adjuvant therapies for reperfusion and seek to establish an optimum treatment strategy based on present evidence. Oral antiplatelet therapy Aspirin irreversibly inhibits cyclooxygenase and thereby blocks eventual production of thromboxane A2, a vaso- constrictor and highly potent stimulant of platelet aggregation (igure 1). Results from the landmark ISIS-2 trial 3 irrefutably showed the eicacy of aspirin to reduce cardiovascular morbidity and mortality when given to patients with suspected acute myocardial infarction, either as a stand-alone therapy or in combination with strepto- kinase. Clopidogrel, a thienopyridine, selectively and irre- versibly binds the platelet surface receptor P2Y12 (also known as P2RY12), which is responsible for initiation of the platelet activation response to the agonist ADP (igure 1). Aspirin and clopidogrel work via complementary mechanisms and provide synergistic inhibition of the platelet aggregation pathway, hence the development of dual antiplatelet therapy for patients with STEMI treated in the thrombolysis era. 4,5 However, a wealth of evidence, reviewed in detail elsewhere, 1,2,6 has left little room for doubt that timely, guideline-mandated primary PCI is the best treatment strategy for patients with STEMI when compared with ibrinolysis. In this context the indication for antiplatelet agents broadens; not only might they ofer beneit as medical therapies in their own right, but they are also needed to prevent the thrombotic–ischaemic complications of coronary stent deployment. In recent years, concerns have grown over the hetero- geneous nature of individuals’ response to clopidogrel. Speciically, several reports have shown a link between high-on-treatment platelet reactivity and subsequent ischaemic complications, including stent thrombosis, in patients given clopidogrel. 7 Because this link is consistent across diferent populations of patients treated with primary PCI, the practice of administration of a standard dose of clopidogrel to all patients, without monitoring of individual responses, might not be robust or optimum. The situation is complicated by the absence of a reliable, quick, easy-to-use, reproducible, and clinically validated point-of-care test for clopidogrel response. 8 Concerns about potential functional resistance to clopidogrel are heightened by the inlammatory milieu in STEMI, a clinical setting in which there is a perceived need for Lancet 2013; 382: 633–43 See Editorial page 572 See Comment page 576 This the second in a Series of three papers about ST-segment elevation myocardial infarction Wessex Cardiothoracic Unit, University Hospital Southampton NHS Foundation Trust, Southampton, UK (Prof N Curzen PhD); Sinai Center for Thrombosis Research, Cardiac Catheterisation Laboratory, Sinai Hospital of Baltimore, Baltimore, MD, USA (Prof P A Gurbel MD); King’s College London BHF Centre of Research Excellence, Cardiovascular Division, The Rayne Institute, St Thomas’ Hospital, London, UK (A Myat MRCP, Prof S R Redwood FRCP); VA Boston Healthcare System, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA (Prof D L Bhatt MD) Correspondence to: Prof Nicholas Curzen, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK nick.curzen@uhs.nhs.uk Search strategy and selection criteria We searched the Cochrane Library, Medline, PubMed, Embase, and references from relevant articles with use of a combination of the search terms “STEMI”, “primary percutaneous coronary intervention”, “aspirin”, “clopidogrel”, “prasugrel”, “ticagrelor”, “cangrelor”, “bivalirudin”, “glycoprotein IIb IIIa inhibitor”, and “manual aspiration thrombectomy”. We largely selected publications from the past 10 years, but did not exclude widely referenced and highly regarded older publications. All studies published in English between Jan 1, 1980, and May 31, 2013, were included in the search.