Aspirin, a derivative of salicylic acid whose origins date back to Hippocrates and a powder he made from the bark and leaves of the willow tree, was first commercially produced in 1900 by Felix Hoffmann, a chemist working for Bayer [1]. Aspirin irreversibly inhibits platelet activation through acetylation of the platelet cyclooxygenase-1 enzyme. Blockage of the cyclooxygenase-1 enzyme prevents the conversion of arachidonic acid to prostaglandin H2, which, in normal conditions, is then converted into thromboxane A2. Platelets possess a thromboxane A2 receptor which, upon binding with thromboxane A2, promotes platelet activation. Thus, as a result of inhibited thromboxane A2 production, platelet activation is inhibited. Because the inhibition of the cyclooxygenase-1 enzyme is irreversible and the platelets cannot create more of the enzyme, the effects last for the lifespan of the platelet (7–10 days).

Aspirin (preferably given prior to the procedure) is indicated as an adjunctive pharmacologic therapy in all coronary interventions. In the pre-stent era, Schwartz et al. evaluated aspirin loading prior to PCI in 376 patients undergoing balloon angioplasty. Patients were randomized to receive either a combination of aspirin/dipyridamole (330 mg/75 mg) or placebo 24 h prior to PTCA. Treatment was continued in patients with a successfully dilated vessel until follow-up angiography, which was performed 4–7 months after PTCA. While the investigators had proposed that the combination of aspirin/dipyridamole would reduce restenosis (it did not), they did demonstrate a significant reduction in the incidence of periprocedural Q wave myocardial infarction (6.9 % in placebo vs. 1.6 % in treatment arm; p = 0.011) [2].

Similar to pre-PCI loading, there is also a single randomized trial for long-term continuation of aspirin post-PCI. In this study, 752 patients were randomly assigned to aspirin (325 mg daily), the thromboxane A2 receptor antagonist sulotroban (800 mg QID), or placebo, started within 6 h before PTCA and continued for 6 months. The results demonstrated that while there was again no difference in restenosis, the rate of myocardial infarction at 6 months was significantly reduced by antithromboxane therapy: 1.2 % in aspirin group, 1.8 % in the sulotroban group, and 5.7 % in the placebo group [3].

The most comprehensive evaluation for dosing of aspirin in the setting of acute coronary syndromes comes from the Antithrombotic Trialists’ Collaboration, which made indirect comparisons between either high or low doses of aspirin. This analysis reviewed 287 studies involving both comparisons of antiplatelet therapy versus control and comparisons of different antiplatelet regimens. While a loading dose of at least 150 mg of aspirin was found to be of significant advantage up front, the benefits of long-term aspirin therapy were similarly independent of whether the maintenance dosing was high dose (>150 mg) or low dose (<150) [4]. Higher doses of aspirin are associated with increased rates of both minor as well as major and intracranial bleeding events. In the CURE study, three aspirin dose groups (≤100, 101–199, and ≥200 mg) were evaluated with or without clopidogrel. Results from this study demonstrated an increased incidence of major bleeding associated with increasing aspirin dose both in the group without concomitant clopidogrel (1.9 % for ≤100 mg, 2.8 % for 101–199 mg, and 3.7 % for ≥200 mg; p = 0.0001) and for the clopidogrel-treated group (3.0 % for ≤100 mg, 3.4 % for 101–199 mg, and 4.9 for ≥200 mg; p = 0.0009). In addition, there was no benefit in cardiovascular death, myocardial infarction, or stoke associated with the higher dose of aspirin [5].

The ACCF/AHA guidelines recommend a loading dose of 325 mg in the setting of STEMI and pre-PCI, and the most updated guidelines now recommend that after PCI, it is reasonable to use 81 mg of aspirin as the maintenance dose [6] (Table 11.1).

In the modern PCI era with both bare-metal and drug-eluting stents, dual antiplatelet therapy with aspirin and a thienopyridine has become the standard of treatment. The thienopyridines that are used post-PCI with aspirin are ticlopidine, clopidogrel, and prasugrel. While aspirin inhibits platelet activation, thienopyridines inhibit both platelet activation and aggregation. These effects on platelets are due both to their inhibition of the activation of the GPIIb/IIIa receptor responsible for platelet linking and the binding of fibrinogen and to their inhibition of platelet ADP receptor P2Y₁₂. The inhibition of the platelet ADP receptor P2Y₁₂ prevents platelet activation and aggregation by downregulating platelet degranulation and the subsequent release of prothrombotic and inflammatory mediators [7] (Fig. 11.1). The mechanism of action of ticlopidine, clopidogrel, and prasugrel all involve inhibition of the platelet ADP receptor P2Y₁₂ by blocking the ADP binding site. Like aspirin, this results in an irreversible inhibition of the platelet, and thus, the effects last for the 7–10 day lifespan of the platelet. The newest oral antiplatelet agent, ticagrelor, is an exception to this irreversible inhibition. Although ticagrelor also blocks the ADP receptor P2Y₁₂ like the thienopyridines, it does so at a different binding site from ADP, and as a result, its effects are reversible [8].

The evidence in favor of the use of thienopyridines in the setting of STEMI and during PCI is supported by significant clinical evidence. The COMMIT study randomized 45,852 patients presenting with acute myocardial infarction to clopidogrel 75 mg daily with no loading dose vs. placebo, in addition to aspirin 162 mg daily. Within the trial, 93 % of the patients presented with ST segment elevation myocardial infarction. In this study, clopidogrel (or placebo) was continued for the duration of the hospitalization or up to 4 weeks with mean treatment duration of 15 days. The composite end point of death, reinfarction, or stroke was significantly reduced in the group receiving clopidogrel as compared to placebo (9.2 % vs. 10.1 %; p = 0.002). There was no significant difference in combined rates for fatal bleeds, blood product transfusion, or intracerebral hemorrhage (0.58 % vs. 0.55 %; p = NS) [9].

Clopidogrel loading prior to PCI has also been demonstrated to be beneficial. The PCI-CLARITY trial, a continuation of the CLARITY–TIMI 28 study, prospectively randomized 1,863 patients undergoing PCI after mandatory angiography in the CLARITY–TIMI 28 trial to either clopidogrel (300 mg oral loading dose followed by 75 mg daily) or placebo in addition to aspirin. Pretreatment with clopidogrel led to a significant reduction in the composite end point of cardiovascular death, recurrent MI, or stroke from PCI to 30 days post-randomization (3.6 % in clopidogrel group vs. 6.2 % in the placebo group; p = 0.008). Pretreatment with clopidogrel also reduced the incidence of MI or stroke prior to PCI (4.0 % vs. 6.2 %; p = 0.03). Importantly, as in the COMMIT study, there was no significant difference in both major and minor bleeding risks (2 % vs. 1.9 %; p = NS) [10].

Prasugrel is one of the newer members of the thienopyridine family. Like clopidogrel, prasugrel is a prodrug that requires conversion to an active metabolite in order to become active. What differentiates prasugrel from clopidogrel is that prasugrel is converted to its active form more quickly and inhibits the ADP binding site of the ADP receptor P2Y₁₂ more potently. The TRITON–TIMI 38 trial evaluated the safety and efficacy of prasugrel in a double-blinded study involving 13,600 patients presenting with acute coronary syndrome undergoing scheduled percutaneous intervention. Patients were randomized to receive either prasugrel (a 60 mg loading dose followed by 10 mg daily) or clopidogrel (a 300 mg loading dose followed by 75 mg daily) for 6–15 months. The primary end point was death from cardiovascular causes, nonfatal MI, or nonfatal stroke. Of the patients included in the study, 26 % presented with STEMI. The primary end point occurred in 12.1 % of clopidogrel patients and 9.9 % of prasugrel patients (p < 0.001). This was driven in part by a significant reduction in the rate of myocardial infarction (9.7 % clopidogrel vs. 7.4 % prasugrel; p < 0.001). Additional benefits of prasugrel included decreased stent thrombosis (3.7 % clopidogrel vs. 2.5 % prasugrel; p < 0.001), and these benefits carried over to the STEMI subset. The benefit of prasugrel in the primary efficacy end point was seen within the first 24 h of randomization and persisted through 15 months of follow-up. Certain subgroups of patients also had a significant benefit with prasugrel, including diabetics and patients receiving Gp IIb/IIIa inhibitors. These improved efficacy outcomes, presumably due to the more potent pharmacokinetics, were however associated with an increased rate of bleeding. Major bleeding was seen in 2.4 % of prasugrel patients compared to 1.8 % seen in the clopidogrel group, including a significant increase in life-threatening bleeding (1.4 % prasugrel vs. 0.9 % clopidogrel; p = 0.01) and fatal bleeding events (0.4 % prasugrel vs. 0.1 % clopidogrel; p = 0.002). Three groups in particular were found to not have a clinical benefit from prasugrel: patients with prior TIA or stroke, patients with a weight <60 kg, and patients >75 years in age. For patients with prior TIA or stroke, there was a net harm from prasugrel administration as compared to clopidogrel [11]. Based on this data, the FDA declared prasugrel to be contraindicated in patients with prior TIA or stroke.

The final current oral antiplatelet agent is ticagrelor, a reversible P2Y₁₂ inhibitor. Ticagrelor was recently evaluated in the PLATO trial, which randomized 18,600 patients presenting with ACS to either clopidogrel (300 mg or 600 mg loading dose followed by 75 mg daily) or ticagrelor (180 mg loading dose followed by 90 mg twice daily). A total of 38 % of patients presented with STEMI. The primary end point of death from vascular causes or cerebrovascular causes, or death from an unknown cause, occurred in 9.8 % in the ticagrelor group vs. 11.7 % in the clopidogrel group (p < 0.001). Furthermore, the composite of all-cause death, MI, or stroke was also reduced in the ticagrelor group (10.2 % vs. 12.3 %; p < 0.001). Similarly, the rate of stent thrombosis was also lower among those patients receiving ticagrelor (1.3 % vs. 1.9 %; p = 0.009). While the rates of major bleeding were similar between the two groups, intracranial bleeding episodes were more common among the ticagrelor group. Lastly, there was no significant difference in the incidence of stroke, including hemorrhagic stroke [12]. Based on the PLATO trial, ticagrelor was FDA approved for patients with acute coronary syndromes in July 2011.

Hirudin is a naturally occurring 65-amino acid polypeptide originally isolated from the medicinal leech, Hirudo medicinalis, and more recently available through recombinant DNA technology. Hirudin blocks the effects of thrombin on the hemostatic system, including the conversion of fibrinogen to fibrin, activation of coagulation factors XI and XIII, positive feedback activation of coagulation factors V and VIII, and thrombin-mediated platelet activation [64]. Administered by intravenous or subcutaneous injection, it has a plasma half-life of approximately 40 min after intravenous injection and 1–3 h after subcutaneous injection. It is primarily excreted renally. The anticoagulant effects of hirudin can be monitored in the laboratory using the activated partial thromboplastin time (aPTT) [65, 66]. Despite having been studied in patients with acute coronary syndromes and percutaneous coronary interventions, it has never assumed use as a frontline therapy.

The OASIS pilot study [67] randomized patients with an acute coronary syndrome without persistent ST elevation to a 72-h infusion of low-dose or medium-dose hirudin infusion or unfractionated heparin (UFH). Hirudin was associated with a reduction in the composite primary outcome of cardiovascular death, myocardial infarction, or refractory angina at 7 days, with a similar incidence of major bleeding. However, the study was not powered for clinical outcomes. In the follow-up OASIS-2 trial, patients with ACS were randomized to medium-dose hirudin or heparin for 72 h. Hirudin was associated with a significantly increased risk of major bleeding compared with UFH [68]. Several large randomized trials followed to evaluate hirudin as an adjunct to thrombolytic therapy in patients with ACS but were terminated because of unacceptably high rates of major hemorrhage [67–71].

Given the bleeding complications, two of the trials, TIMI9A and GUSTO-IIb [67, 68], were restarted with lower doses of hirudin and UFH. The GUSTO-IIb trial showed a small reduction in the primary composite outcome of death or myocardial infarction with hirudin compared with heparin at 30 days. There was a reduction in death or myocardial infarction with hirudin during the first 24 h, and subgroup analysis suggested a highly significant 39 % reduction in death or myocardial infarction at 30 days in the hirudin-treated group. However, in the TIMI-9B trial, no benefit of hirudin over UFH was observed. Neither TIMI-9B nor GUSTO-IIb demonstrated an increase in major or intracranial bleeding with hirudin. Similarly, the HIT-4 trial failed to show any difference between clinical outcomes or major bleeding when comparing hirudin with heparin as adjunctive therapy to streptokinase in acute myocardial infarction [72].

Due to the lack of convincing evidence supporting efficacy of hirudin over heparin and the concern for intracranial bleeding, it was never approved for use in percutaneous coronary interventions. Its only clinical role remains as anticoagulation in patients with heparin-induced thrombocytopenia.

Argatroban is a synthetic, small-molecule direct thrombin inhibitor that is approved in the USA for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia (HIT) and for anticoagulation of HIT patients undergoing PCI [73]. Argatroban is parenteral and the polypeptide binds to and inhibits the active site of thrombin. Unlike bivalirudin, argatroban is predominantly eliminated through the liver and plasma concentrations are not influenced by renal function [72]. It has a rapid onset of action and a half-life of 45 min (extended to 2.5 h in patients with hepatic impairment) [74, 75]. Argatroban increases the activated partial thromboplastin time, prothrombin time, and thrombin clotting time in a dose-dependent manner. The activated partial thromboplastin time is commonly used to monitor its anticoagulant effects. Like bivalirudin, argatroban has no known reversal antidote.