Aspirin (acetylsalicylic acid or ASA) is a cornerstone of ACS therapy. Several clinical trials and subsequent meta-analyses have shown that ASA lowers ischemic morbidity and mortality rates by as much as 50 % in ACS [3–7]. The enzyme cyclooxygenase-1 (COX-1) is responsible for the conversion of arachidonic acid into TXA-2 within platelets, a potent platelet aggregator and endothelial vasoconstrictor which subsequently facilitates the activation of other platelets. Aspirin exerts its antiplatelet effects by irreversibly inhibiting the COX-1 enzyme, effectively blocking the synthesis of TXA-2. Since platelets do not synthesize new enzymes, the functional defect induced by aspirin therapy persists for the life of the platelet. Initial therapy in any suspected or confirmed NSTE ACS presentation should include a 325 mg dose of non-enteric-coated chewable ASA to allow for rapid absorption, followed by indefinite low-dose maintenance therapy (81 mg daily) for those patients with confirmed ACS. Recent evidence has shown there is no benefit to a higher 325 mg daily maintenance dose, and it is associated with higher rates of bleeding complications [8].

At the recommended doses used in ACS, aspirin has few notable drug interactions or significant adverse events. The adverse effects of aspirin are dose related and are extremely rare at low dosages (exact quantification of frequency is not possible). As with all antiplatelet and anticoagulant agents discussed in this chapter, bleeding is associated with aspirin use and may occur at virtually any site. Multiple variables affect an individual patient’s bleeding risk, including dosage, concurrent use of multiple antithrombotic agents, which affect hemostasis, and underlying patient comorbidities. Patients who develop GI adverse effects should be treated with a proton pump inhibitor, and many are then able to tolerate low-dose aspirin therapy. True hypersensitivity reactions (angioedema, bronchospasm, and/or hives) are very rare; however, aspirin desensitization can be performed, if present.

The addition of a second antiplatelet agent to aspirin (“dual antiplatelet therapy”) marked a significant advance in the treatment of ACS. Several oral medications are available to inhibit platelet activity at the level of the P2Y12 ADP receptor that provides an additive antiplatelet effect to the thromboxane A2 inhibition by aspirin. There are three FDA-approved thienopyridines (clopidogrel, prasugrel, and ticlopidine) which irreversibly inhibit ADP-mediated platelet activation and aggregation by binding to the platelet P2Y12 receptor. Ticlopidine was the first approved agent; however, due to its delayed onset of action and unfavorable hematologic adverse events, it is no longer used in contemporary treatment of NSTE ACS. Clopidogrel, considered a “second-generation” agent, and the “third-generation” prasugrel and ticagrelor (a reversible P2Y12 antagonist) are the currently used agents.

Clopidogrel, an irreversible P2Y12 receptor antagonist, is a prodrug, which requires conversion into its active metabolite by the hepatic cytochrome P450 2C19 isoenzyme. It has a variable time to peak effect of approximately 2–4 h depending on the loading dose chosen [9, 10]. The foundation of its use in the NSTE ACS population was established by the Clopidogrel to Prevent Recurrent Events (CURE) trial, which demonstrated a 20 % relative reduction (9.3 % vs. 11.4 %, P < 0.001) of composite endpoints including cardiovascular death, nonfatal MI, and stroke, at the expense of more major bleeding (3.7 % vs. 2.7 %, P = 0.001). The subsequent Clopidogrel and Metoprolol in Myocardial Infarction (COMMIT) trial also demonstrated a highly significant 9 % proportional reduction in death, reinfarction, or stroke (9.2 % vs. 10.1 %; P = 0.002) when clopidogrel was added to standard aspirin therapy in a predominantly STEMI patient population (93 % STEMI, 7 % NSTE ACS) [11]. Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor should be initiated as soon as possible after presentation for a patient with ACS. As clopidogrel may particularly increase bleeding in patients who undergo coronary artery bypass surgery (CABG) [12], guidelines recommend stopping clopidogrel at least 5 days prior to CABG. Concerns regarding CABG-related bleeding have led some clinicians to delay clopidogrel administration until a patient’s coronary anatomy is angiographically defined. Unless there is a very high suspicion that the patient will require urgent surgery, however, we advocate for the early administration of clopidogrel so as to not withhold its anti-ischemic benefits from the vast majority of patients with NSTE ACS who will not require urgent surgical revascularization [13].

The required activation of the prodrug clopidogrel by the hepatic cytochrome P450 2C19 (CYP2C19) system creates important therapeutic considerations. Genetic polymorphisms of CYP2C19 and some medications, such as omeprazole, have been associated with pharmacokinetic/pharmacodynamic (PK/PD) effects on clopidogrel activation. Observational studies have suggested an association with worse outcomes in patients with slow conversion; however, randomized studies using genetic polymorphisms and platelet function testing to guide more aggressive antiplatelet therapy have thus far failed to show a benefit of treatment modifications based upon such testing [14–16]; we do not recommend routine use of functional or genetic testing in routine clinical practice. There has only been one randomized controlled trial testing coadministration of clopidogrel and omeprazole, and it did not show an effect of omeprazole on cardiovascular outcomes [17].

The most common adverse effects of clopidogrel are bleeding and minor dermatologic reactions (rash, pruritus, or similar in less than 5 % of patients). As with all antiplatelet and anticoagulant agents discussed in this chapter, the risk of bleeding is increased by combining antithrombotic agents, and multiple variables will affect an individual patient’s bleeding risk. In our practice, we do not consider any drug interactions to present an absolute contraindication to clopidogrel usage, including omeprazole based on the recent evidence presented above. Experience with clopidogrel in the setting of severe liver dysfunction is limited, and while not an absolute contraindication to its use, caution and extra monitoring for bleeding may be considered in patients with severe hepatic impairment.

Prasugrel is a third-generation thienopyridine that irreversibly inhibits the P2Y12 receptor. While it is also a prodrug requiring hepatic metabolism to its active metabolite, this conversion requires fewer enzymatic steps and thus occurs with a more rapid and less variable pharmacodynamic profile than with clopidogrel [18]. Its metabolism is not dependent on the CYP2C19 isoenzyme, and proton pump inhibitors are not known to have any clinically significant PK/PD interaction with prasugrel. The foundation for prasugrel’s use in NSTE ACS was established by the TRITON-TIMI 38 trial, which demonstrated a lower rate of composite endpoints, including cardiovascular death, nonfatal MI, and nonfatal stroke (9.9 % vs. 12.1 %, P < 0.001), as well as a lower risk of in-stent thrombosis in patients who underwent percutaneous intervention (1.1 % vs. 2.4 %, P < 0.001); however, these ischemic benefits were again at the expense of a higher rate of non-CABG major bleeding including fatal bleeding (2.4 % vs. 1.8 %, P = 0.03) [19]. A notable subgroup of patients who had a net negative outcome was those with a prior history of stroke or transient ischemia attack (TIA), and prasugrel use in such patients is not recommended. Additional populations in which special caution is advised include patients over 75 years of age and patients weighing <60 kg as increased bleeding complications were noted in these groups. In an important distinction from the CURE trial, NSTE ACS patients in TRITON-TIMI 38 only received the prasugrel loading dose after their coronary anatomy was angiographically defined and percutaneous revascularization planned, and in most cases prasugrel should be held for 7 days prior to CABG due to the high bleeding risk. The trial did not evaluate prasugrel for an early conservative management strategy for NSTE ACS. The subsequent TRILOGY-ACS trial found no difference in the rates of death, MI, or stroke at 12 months with clopidogrel versus prasugrel in medically managed patients with high-risk NSTE ACS [20].

Similar to clopidogrel, the most common adverse effects of prasugrel are bleeding and minor dermatologic reactions (e.g., rash, in less than 5 % of patients). Labeling also notes a less than 5 % incidence of other minor reactions including headache, nausea, dizziness, and fatigue. As with all antiplatelet and anticoagulant agents discussed in this chapter, the risk of bleeding is increased by combining antithrombotic agents, and multiple variables will affect an individual patient’s bleeding risk. In our practice we do not consider any drug interactions to be an absolute contraindication to prasugrel; however, like clopidogrel, the use of prasugrel in the setting of severe liver dysfunction has not been well studied.

Ticagrelor is a third-generation reversible P2Y12 antagonist that, unlike the thienopyridines, is an active drug and does not require hepatic conversion to an active metabolite. It exhibits the most rapid onset, greatest inhibition, and least individual variability of the oral P2Y12 agents [21]. The foundation of its use in NSTE ACS was established by the PLATO trial in which ticagrelor demonstrated a lower rate of composite cardiovascular events (death, MI, and stroke 9.8 % vs. 11.7 %, P < 0.001) with fewer cases of in-stent thrombosis and without a significantly increased risk of major bleeding compared to clopidogrel. There was, however, a higher incidence of non-CABG major bleeding including intracranial hemorrhage in the ticagrelor group (4.5 % vs. 3.8 %, P = 0.03) [22]. Because of its reversible pharmacokinetics, its antiplatelet effects attenuate more quickly than the thienopyridines. Therefore, while it is still recommended to hold ticagrelor for 5 days prior to CABG, experienced surgical centers can often operate earlier with acceptable bleeding outcomes.

The most common adverse effect reported for ticagrelor is dyspnea in up to 15 % of patients. Ticagrelor-related dyspnea does not require specific treatment nor does it mandate therapy interruption. While not completely understood, this is thought to be a bradykinin-mediated symptom and rarely is severe enough to require discontinuation of ticagrelor therapy. Like prasugrel, ticagrelor is also associated with low rates of minor dermatologic reactions (e.g., rash) and nonspecific symptoms such as headache, nausea, dizziness, and fatigue in less than 5 % of patients. As with all antiplatelet and anticoagulant agents discussed in this chapter, the risk of bleeding is increased by combining antithrombotic agents, and multiple variables will affect an individual patient’s bleeding risk. In contrast to the thienopyridines, the use of ticagrelor is explicitly contraindicated in patients with severe hepatic dysfunction, and another agent should be considered. Similar to clopidogrel and prasugrel, the use of ticagrelor in moderate liver dysfunction has not been well studied. Ticagrelor has a notable drug interaction with other agents affecting CYP3A4 metabolism. Specifically, concomitant use of ticagrelor should be avoided with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, dexamethasone, phenobarbital, and phenytoin) or strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, nefazodone).

The glycoprotein IIb/IIIa receptor inhibitors (GPI) are intravenous medications that inhibit platelet aggregation and thrombus formation by preventing the binding of fibrinogen or circulating vWF on the platelet surface. The three agents currently approved in the USA are abciximab, eptifibatide, and tirofiban. Abciximab is a Fab fragment of a humanized murine antibody that exhibits a very strong affinity for the glycoprotein receptor. While it has a short plasma half-life (approximately 30 min), abciximab’s strong binding results in platelet inhibition continuing for days after the infusion is stopped. Eptifibatide, a small-molecule cyclic heptapeptide, and tirofiban, a synthetic nonpeptide antagonist, both reversibly inhibit the IIb/IIIa receptors on the surface of platelets with a shorter duration of action (half-life approximately 2 h with platelet activity normalizing approximately 4 h after discontinuation).

At proper doses, all three GPI agents are very potent inhibitors of platelet aggregation; however, their use has been diminishing as much of their supporting evidence came prior to the contemporary era of routine oral dual antiplatelet therapy. Several, large randomized control trials have investigated GPI use in multiple contexts, including ACS and elective percutaneous intervention (PCI). When reviewing this literature, it is important to carefully understand the indications and the patient populations studied in each of these trials as they influence the noted differences in results, and the relative benefits and risks may vary significantly based on the context in which the medication is being given. Table 23.2 presents a brief summary of select, landmark GPI trials. Multiple trials examining abciximab and eptifibatide with aspirin and heparin in high-risk and NSTE ACS patients undergoing PCI found 30–50 % reductions in short-term ischemic endpoints at the expense of increased bleeding [23, 28, 31, 32]. While bleeding complications were reduced by adjustments in weight-based dosing of GPIs and concurrent lowering of heparin dosing, minor bleeding and the risk of thrombocytopenia remained increased. In NSTE ACS patients managed medically, again prior to the routine use of P2Y12 antagonists, trials with eptifibatide and tirofiban showed a reduction in ischemic endpoints; however, the magnitude of benefit was lower than with patients undergoing PCI [26, 29]. An important 2002 meta-analysis reinforced the benefits of GPI in NSTE ACS patients treated with aspirin and heparin who did not undergo early revascularization (conservative/medical management), analyzing six trials enrolling 31,402 patients. It found a 9 % reduction in the odds of a combined endpoint of death or myocardial infarction at 30 days with GPI compared with placebo or control (10.8 % vs. 11.8 %; odds ratio 0.91 [95 % CI 0.84–0.98]; p = 0.015); however, major bleeding complications were increased by GPI (2.4 % vs. 1.4 %; p < 0.0001), and the benefits appeared to be limited to the highest risk patients [33]. More recent trials reflecting the routine use of clopidogrel early in the course of treatment for patients with NSTE ACS or bivalirudin in PCI did not demonstrate an incremental benefit for ischemic outcomes with the routine addition of GPI [34–37]. Therefore, current guidelines call for dual, not triple, antiplatelet therapy (ASA and usually P2Y12 antagonists rather than GPI), with the addition of GPI reserved for patients who remain unstable, have a large thrombus burden on angiography, or have very high-risk clinical features. Dose reduction must be used in patients with significant renal impairment receiving either eptifibatide or tirofiban, and dialysis is an absolute contraindication to eptifibatide use.

As with all antiplatelet and anticoagulant agents discussed in this chapter, the risk of bleeding is increased by combining antithrombotic agents, and multiple variables will affect an individual patient’s bleeding risk. In our practice we do not consider any drug interactions to be an absolute contraindication to use with the GPI agents. Labeling for abciximab, eptifibatide, and tirofiban reflects adverse effects to include the rare occurrence of nausea and other GI intolerances.

Unfractionated heparin (UFH) is a glycosaminoglycan of varying molecular weights that accelerates the action of antithrombin (formerly known as antithrombin III), the enzyme that inactivates thrombin and factor Xa, thereby preventing conversion of fibrinogen to fibrin. Dosing is weight based, and a traditional NSTE ACS bolus of 60 units/kg (not to exceed 4,000 units) has a dose-dependent half-life of 30–60 min. The foundation for its use in NSTE ACS was highlighted by a meta-analysis of six relatively small randomized controlled trials that demonstrated a 33 % reduction in death or MI among unstable angina patients treated with aspirin plus heparin compared to those treated with aspirin alone [38]. Select features from these six historical trials, which formed the basis for the use of UFH in NSTE ACS, are presented in Table 23.3.

A distinct advantage of UFH is that its anticoagulant effect can be followed with routine activated partial thromboplastin times (aPTT) or point-of-care activated clotting times (ACT) in the catheterization laboratory. Additional advantages include its widespread availability, low cost, rapid clearance after the infusion is discontinued, and the ability to reverse its anticoagulant effects with protamine in urgent situations. It is well suited for the use in both medically managed patients and those undergoing early PCI. Potential disadvantages include the higher incidence of heparin-induced thrombocytopenia with UFH compared to other heparin preparations, platelet activation, inability to inhibit clot-bound thrombin due to steric hindrance, circulating inhibitors, and inconsistent PK/PD due to nonspecific binding to multiple other proteins.