For a number of years, the debate on the optimal anticoagulation for patients with acute coronary syndromes (ACS) has lingered. From its beginning, there has been consternation about the role of unfractionated heparin (UFH) in unstable angina, which appeared to have considerable backing from the Montreal Heart Study and an overview of all of the randomized trials conducted by Oler et al.(1,2) Ultimately, the weight of the evidence supported the use of UFH as a background/foundation therapy, a conclusion reflected by the American College of Cardiology (ACC) and American Heart Association (ARA) guidelines for acute coronary syndromes published in 2000.(3) At the same time that there was increasing acceptance of the importance of UFH use in this setting, newer randomized trials were launched to directly compare low-molecular-weight heparin (LMWH) with UFH.(4) In general, these comparative trials were conducted with various forms of LMWH, including nadroparin, dalteparin, and enoxaparin. Only enoxaparin was demonstrated to have superior efficacy when directly compared with UFH.(4) Even this point was contentious, as some overview articles challenged a drug-specific effect and underscored the overall lack of proof across the class of LMWHs.(5) Nevertheless, two randomized trials assessing a total of 7,081 patients at 6 weeks after presentation of an ACS, ESSENCE and TIMI 11B, each provided evidence of the superiority of enoxaparin over UFH using a triple end point of death, myocardial infarction (MI), or recurrent ischemia, and in aggregate, there was an 18% reduction of death or MI.(6) With this more rigorous end point of death or MI fulfilled by combining the two trials, and the directionality and magnitude of benefit replicated in both, the new 2002 ACC/AHA guidelines changed enoxaparin's status to Class IIa because of evidence that this agent was preferred over UFH.(7) Up to this point, trials of anticoagulation. were predominantly in the context of medical management, without aggressive use of coronary angiography and revascularization. But many new trials were conducted using platelet glycoprotein (GP) IIb/IIIa inhibitors, and dual oral antiplatelet therapy with aspirin and clopidogrel.(8-11) Accordingly, the relative merits of enoxaparin versus UFH needed to be assessed in the setting of early coronary revascularization and with conjunctive, evidence-based medical therapy. This comparison and context were the principal objectives of the SYNERGY trial, which will be reviewed here.(12) The purpose of this article win be to provide a critique of SYNERGY, A to Z, and the systematic overview of all of the trials that compared UFH with enoxaparin.(12-14)
