Acute coronary syndromes (ACS), including unstable angina (UA), non–ST-segment elevation myocardial infarction (NSTEMI), and ST-segment elevation myocardial infarction (STEMI), represent the clinical complications of atherosclerosis mediated by plaque rupture1 and superficial endothelial cell erosion2 that produce nonocclusive and occlusive thrombus formation. NSTEMI accounts for more than 1.6 million annual admissions, representing up to 75% of all cases of myocardial infarction (MI) in US hospitals.3 Appropriate care for patients with ACS is informed by a wealth of recent randomized controlled trials, the findings of which have been summarized into national clinical practice guidelines by the American College of Cardiology/American Heart Association (ACC/AHA),3-5 the American College of Chest Physicians (ACCP),6-8 and the European Society of Cardiology (ESC).9,10 This chapter will review the pharmacology of antiplatelet, anticoagulant, and fibrinolytic agents and also focus on evidence-based recommendations for antithrombotic therapy for ACS. Since the prior edition, assessing the net clinical benefit of a particular antithrombotic agent—namely, balancing efficacy and safety (ie, bleeding)—has moved front and center in our analysis of clinical trials.11-13 Rather than focusing solely on ischemic events (eg, recurrent MI, stroke), attention has shifted to the importance of bleeding, given its high prevalence and adverse impact on mortality, which is likely secondary to multiple factors including impaired oxygen delivery, adverse effects of transfusion (ie, proinflammatory, old vs new blood), and cessation of antithrombotic medications.11,12,14 There are important sex- and age-related factors that promote bleeding due to excessive dosing.15,16 Understanding these pharmacologic considerations is essential for the practicing clinician. Finally, guideline adherence rate is significantly associated with in-hospital mortality. In an observational analysis of hospital care in 350 academic and nonacademic US centers of 64,775 patients enrolled in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) trial, every 10% increase in composite adherence at a hospital was associated with an analogous 10% decrease in its patients' likelihood of in-hospital mortality.17 Thus a thorough knowledge of pharmacologic therapy and guideline-recommended treatments is the foundation for optimizing outcomes for patients with ACS.
Currently, there are three different classes of antiplatelet agents that are approved for the treatment and/or prevention of recurrent events in patients with ACS: cyclooxygenase-1 (COX-1) inhibitors (aspirin), adenosine diphosphate (ADP) P2Y12 receptor antagonists (thienopyridines and nonthienopyridines), and glycoprotein (GP) IIb/IIIa inhibitors. These agents are mostly used in combination in patients presenting with an ACS, in particular those undergoing percutaneous coronary intervention (PCI). Details of each of these classes of antiplatelet agents and their indications for use are provided below. In addition, limitations of the most frequently used oral antiplatelet agents (antiplatelet drug "resistance"), as well as novel antiplatelet therapies under advanced clinical investigation, which may represent treatment alternatives to current strategies, are described.
Mechanism of Action and Pharmacokinetic/Pharmacodynamic Profile
Aspirin (acetylsalicylic acid [ASA]) is ...