Cardiovascular disease manifestations are currently the leading cause of death in industrialized countries and are expected to become so in emerging countries by 2020. In particular, coronary artery disease is the most prevalent manifestation and is associated with high mortality and morbidity worldwide. Coronary artery disease is almost always caused by coronary atherosclerosis with or without luminal thrombosis and vasospasm. Atherosclerosis alone may cause stable angina but is rarely fatal. In contrast, arterial thrombosis occurring as a consequence of atherosclerotic plaque disruption or rupture plays a major role in the pathogenesis of life-threatening acute coronary syndromes (ACSs), including unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI). A nonocclusive or transiently occlusive thrombus most frequently underlies a UA/NSTEMI presentation, whereas a more stable and occlusive thrombus is typically found in patients with STEMI. A critical thrombotic component is also frequent in culprit lesions responsible for out-of-hospital cardiac arrest and sudden coronary death. In the United States, STEMI comprise 25% to 40% of myocardial infarction presentations, with in-hospital mortality of approximately 5% to 6%, whereas in Europe, the prevalence is around 66 STEMI/100,000/year, with in-hospital mortality between 6% and 14%. UA/NSTEMI presentations remain more frequent than STEMI and are a more common presentation in the elderly.

Professional cardiovascular societies in the United States and Europe constantly update practice guidelines for the management of patients with ACS, for both UA/NSTEMI and STEMI, with the aim of putting together available scientific evidence and to provide clinical practice recommendations for the treatment of these disease manifestations. The ever-rising knowledge of the pros and cons of currently available treatment strategies and the introduction of novel therapies have led to marked reductions in clinical event rates but also to an evolution in definitions and concepts. One of the biggest challenges for guidelines is to remain updated according to the most recent findings, given the rapid pace at which new evidence from clinical trials and registries becomes available. This is also pivotal for clinicians, who may hesitate to apply in their daily practice such novel information without endorsement from professional societies.

Antithrombotic therapy is pivotal in the acute and long-term treatment of patients with ACS presentations. Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been the cornerstone of treatment for patients with ACS for several years. Despite the efficacy of this strategy, patients continue to experience adverse ischemic events, and therefore, new antiplatelet agents have been developed. Prasugrel and ticagrelor are faster and more potent P2Y ₁₂ receptor inhibitors that have shown greater antiplatelet effect and better clinical outcomes compared with clopidogrel in patients with ACS. Their use has been recently incorporated in practice guidelines, but how to choose one agent over the others is only partially addressed and is mainly left to physicians’ discretion, based on patient characteristics or specific contraindications. Similarly, with the availability of alternative anticoagulants, such as bivalirudin and fondaparinux, in addition to the more established unfractionated heparin and enoxaparin, it is not always clear which is the best pharmacologic combination to be used in different clinical settings. Other areas of unmet need related to antiplatelet therapy in patients with ACS are the best duration of DAPT after the acute event and the role of pretreatment before angiography. Recommendations on these issues are available in the guidelines, but they are not always at pace with emerging knowledge of antithrombotic treatment strategies.

The choice of the best stent for patients undergoing percutaneous coronary intervention (PCI) is another area of uncertainty. Recent findings have shown an increase in the safety of drug-eluting stents (DESs), with similar or even lower rates of stent thrombosis and greater efficacy compared with bare-metal stents, leading to overall better outcomes with new-generation DESs. This may potentially shift the stent choice toward DES in clinical settings in which bare-metal stents are recommended, such as patients with poor compliance or high bleeding risk.

Additional areas of unmet need for the mid- or long-term management after an ACS that need to be emphasized are the use of a wearable cardioverter-defibrillator in patients with low ejection fraction after an acute event, who need to be evaluated after 30 to 40 days for permanent defibrillator implantation, as well as how to improve patients’/physicians’ adherence to guideline-recommended therapy, which is known to be low at long-term follow-up.

Timely reperfusion with primary PCI has been the key goal in the management of patients with STEMI, and door-to-balloon times have decreased over the past years, leading to a significant decrease in adverse outcomes. However, recent findings have shown that a further reduction in door-to-balloon time is not associated with a reduction in mortality rate. These findings highlight the need to develop new strategies to reduce interhospital transfer time or time from symptom onset to first medical contact, in order to improve prehospital timing, a concept only partially addressed in guidelines. In this setting, recent studies have demonstrated that when primary PCI cannot be performed in a timely fashion, the use of a pharmacoinvasive approach can be considered safe and effective. However, there are remaining challenges with regard to adjunctive pharmacotherapy for patients undergoing a pharmacoinvasive strategy with fibrinolytics. In particular, how to embrace the use of bivalirudin and the novel oral P2Y ₁₂ receptor antagonists prasugrel and ticagrelor in patients proceeding with PCI remains unclear. Other areas of uncertainties on how to incorporate guideline recommendations with more recent evidence from clinical trials in the management of STEMI are the use of thrombus aspiration devices and the use of complete versus incomplete or staged revascularization in patients with multivessel disease, which represent 65% of patients undergoing primary PCI.

In summary, the large number of clinical trials and registries conducted in recent years in patients with ACS has allowed defining strategies associated with better outcomes. Accruing expertise in treating these patients along with the introduction of novel devices and pharmacologic agents has made ACS management an ever-evolving field in cardiovascular care. New evidence-based recommendations translated into clinical practice represent the key to interpretation of American and European guidelines. However, some pharmacologic and procedural choices still remain not fully investigated, leading to inhomogeneous treatments. Therefore, new studies designed to provide clinical practice and patient-centered recommendations addressing unmet needs in terms of duration of DAPT and drugs and devices of choice according to clinical setting are needed.

In this supplement, an overview of antithrombotic therapies in UA/NSTEMI and STEMI practice guidelines from professional societies in the United States and Europe is provided. Emphasis on differences between guideline recommendations, areas of uncertainty and possible improvements, as well as how guidelines can be translated into clinical practice are discussed.