Aspirin, or acetylsalicylic acid, is a prodrug of salicylic acid that blocks platelet activation. Aspirin irreversibly inhibits both cyclooxygenase enzymes (COX-1, COX-2), reducing prostaglandin and TXA byproducts generated from arachidonic acid. Thromboxane A₂ stimulates platelet activation, aggregation, and recruitment. COX-1 enzymes are present in most tissues, but larger amounts are found in the stomach, kidneys, and platelets. The prostaglandin products of COX enzyme activity provide protection from gastrointestinal mucosal injury. COX-2 is found in both nucleated and nonnucleated cells and is responsive to inflammatory stimuli. Inhibition of COX-1 appears to be the primary mechanism by which aspirin inhibits hemostasis. The acetylation of platelet COX-1 enzymes by aspirin causes inhibition of platelet TXA₂ production. The irreversible antiplatelet effect lasts for the life of platelet (7 to 10 days). Saturation of the mechanism occurs at doses as low as 30 mg. Large doses of aspirin (> 3,000 mg daily) are required to inhibit COX-2 and produce systemic anti-inflammatory effects. Consequently, there is a 50- to 100-fold variation between the daily doses required to suppress inflammation and inhibit platelet function [7,8].

Enteric-coated and delayed release formulations have diminished bioavailability, take 3 to 4 hours to reach peak plasma levels, and have delayed onset. Rectally administered aspirin has variable absorption with a bioavailability of 20% to 60% over a 2- to 5-hour retention time [9]. For acute thrombosis, immediate-release aspirin is preferred [10].

The optimal aspirin dose that maximizes efficacy and minimizes toxicity is controversial. Evidence-based recommendations vary from 75 to 325 mg daily. There is currently no data suggesting inferiority of lower (75 to 100 mg) to higher (> 100 mg) maintenance dosing in preventing thromboembolic events [11].

Recurrent vascular thrombotic episodes despite aspirin therapy occur at rates between 2% and 6% of patients per year [4]. Aspirin resistance occurs in 5.5% to 45% of aspirin-treated patients. Possible mechanisms of aspirin resistance
include extrinsic factors (compliance, absorption, dosage formulation, and smoking) and intrinsic factors (pharmacodynamic alterations, receptor polymorphisms, upregulation of nontargeted platelet activation pathways). In clinical trials, aspirin resistance has been associated with an increased risk of death, acute coronary syndromes (ACS), and stroke [5,12,13].

Aspirin is indicated for the primary and secondary prevention of arterial and venous thrombosis (Table 110.1). Aspirin is effective in reducing atherothrombotic disease morbidity and mortality in ACS, stable angina, coronary bypass surgery, peripheral arterial disease (PAD), transient ischemic attack, acute ischemic stroke, and polycythemia vera. A meta-analysis of 145 randomized studies in patients with coronary artery and cerebrovascular disease demonstrated that aspirin 75 to 300 mg per day reduced the risk of nonfatal myocardial infarction (MI) by 35% and the risk of vascular events by 18% [14]. Aspirin provides effective thromboprophylaxis in patients on warfarin with prosthetic heart valves and in patients with nonvalvular atrial fibrillation [15].

Aspirin increases the incidence of major, gastrointestinal, and intracranial bleeding [15]. The recommended interval for discontinuation of aspirin prior to elective surgery or procedures is 7 to 10 days. Therapy can be resumed approximately 24 hours or the next morning after surgery when there is adequate hemostasis [16]. For patients exhibiting clinically significant bleeding or requiring emergent surgery, platelet transfusion may be warranted. Intravenous desmopressin antagonizes aspirin’s effect, suggesting a role in emergent situations as well [17].

Aspirin produces gastrointestinal ulcerations and hemorrhage through direct irritation of the gastric mucosa and via inhibition of prostaglandin synthesis. Aspirin, in recommended doses, increases the risk of gastrointestinal bleeding 1.5- to 3-fold [14,18]. Enteric-coated and buffered aspirin doses ≤ 325 mg do not reduce the incidence of gastrointestinal bleeding [19]. Aspirin-induced gastric toxicity can be prevented with concurrent use of acid-suppressive therapy [20].

Underlying aspirin allergy can exacerbate respiratory tract disease, angioedema, urticaria, or anaphylaxis and is estimated
to occur in 10% of the general population. These patients may be converted to alternative antiplatelet therapies. Leukotriene-modifying agents may reduce aspirin-provoked respiratory reactions but do not eliminate the risk. For patients with a compelling indication for therapy, aspirin desensitization may be considered [21].

P2Y₁₂ inhibitors prevent platelet activation by blocking ADP binding to P2Y₁₂ receptors. This action prevents activation of the GP IIb/IIIa receptor complex on the platelet surface [10].

Thienopyridine derivatives, clopidogrel, prasugrel, and ticlopidine, are prodrugs requiring hepatic activation via the cytochrome P450 (CYP450) isoenzyme system (Table 110.2). Metabolism by CYP450 plays a key role in the onset of action, potency, and drug interaction profile of these agents [22,23]. A loading dose provides a rapid increase in plasma concentration and a faster onset of action. Both clopidogrel and ticlopidine require a two-step activation process via CYP450. Prasugrel undergoes one-step oxidation by multiple CYP450 isoenzyme pathways which are believed to be responsible for its more predictable action.

While thienopyridine metabolites have a short plasma elimination half-life (1 to 8 hours), their irreversible activity at P2Y₁₂ receptors spans the life of the platelet (7 to 10 days). The onset of action, duration of antiplatelet effect, and unpredictable levels of platelet inhibition have led to the development of newer agents [24,25,26]. Three investigational nonthienopyridine derivatives are currently under investigation for the management of ACS. These agents do not require hepatic activation resulting in immediate, short-acting, dose-dependent inhibition of platelet aggregation [26].

Resistance to clopidogrel occurs in 4% to 34% of patients and depends on the agent, type, and timing of platelet function test, as well as underlying comorbidities such as diabetes and obesity [23]. Possible mechanisms of P2Y₁₂ inhibitor resistance include extrinsic factors and intrinsic factors. Recent literature highlighted the importance of genetic and drug-induced alterations of CYP3A4 enzymes, the pathway responsible for thienopyridine activation [27]. Clopidogrel resistance has been associated with an increased risk of death, MI, and stroke. For patients with presumed or confirmed clopidogrel resistance, maintenance dosing up to 150 mg daily or use of more potent agents may be necessary, particularly in patients with in-stent thrombosis [27].

Monitoring the antiplatelet effect of P2Y₁₂ inhibitors using platelet function testing is an evolving area of research [27]. The high incidence of varied responses to thienopyridines due to CYP450 polymorphisms and potential drug interactions have suggested a strategy for improving response by using point-of-care platelet function testing.

P2Y₁₂ inhibitors are indicated for primary and secondary thrombosis prevention in a variety of disease states (Table 110.3). Ticlopidine reduces thrombotic events in patients with stroke, but is associated with neutropenia, thrombocytopenia, and thrombotic thrombocytopenic purpura [28]. Clopidogrel is indicated alone or in combination with aspirin for primary and secondary prevention of ischemic events in ACS, PAD, stroke, and coronary artery disease. Prasugrel is indicated alone or in combination with aspirin for the prevention of thrombotic cardiovascular events, including in-stent
thrombosis, in ACS patients who are managed with percutaneous coronary intervention (PCI) [23].

The incidence of major bleeding with P2Y₁₂ inhibitors varies between agents, dosing, patient populations, and concomitant antithrombotic therapies. Gastrointestinal hemorrhage is a common complication of P2Y₁₂ inhibitor therapy [20]. Endoscopic evaluations at 1 week demonstrated less gastrointestinal damage with clopidogrel 75 mg daily than with aspirin 325 mg daily [29]. For patients exhibiting clinically significant bleeding, platelet transfusion may be warranted.

P2Y₁₂ inhibitors should be avoided in patients undergoing neuraxial analgesia due to the risk of subdural hematoma [30]. Therapy should be discontinued 7 to 10 days prior to elective surgery or invasive procedure and resumed approximately 24 hours or the next morning after surgery.

GP IIb/IIIa receptors are expressed on the platelet surface, with approximately 50,000 to 80,000 copies per platelet. Blocking GP IIb/IIIa receptors prevents platelet activation, aggregation, and fibrinogen-mediated platelet to platelet bridging.

Intravenous GP IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban) vary in their structure and pharmacokinetic properties (Table 110.4) [10,31]. Although the exact threshold required for efficacy with these agents has not been established, > 80% platelet inhibition is thought to be a target associated with adequate antiplatelet activity in patients with ACS and in those undergoing PCI [32].

Abciximab is a human–murine chimeric monoclonal antibody that demonstrates a dose-dependent inhibition of GP IIb/IIIa receptors. After an initial intravenous bolus and infusion, the onset of platelet inhibition is rapid (5 minutes) and 80% to 90% of ADP-induced platelet aggregation is suppressed [31]. Abciximab has a strong affinity for the receptor, resulting in occupancy that persists for weeks. Once discontinued, platelet function recovers gradually, with bleeding time normalizing at 12 hours and ADP-induced aggregation returning at 24 to 48 hours [31,32].

Both eptifibatide, a synthetic peptide, and tirofiban, a synthetic small molecule, demonstrate high selectivity, but reduced affinity for the GP IIb/IIIa receptor when compared to abciximab. Both exhibit platelet inhibition that is linear and dose dependent. An intravenous eptifibatide or tirofiban bolus dose followed by an infusion provides > 80% inhibition of ADP-induced platelet aggregation. For patients undergoing PCI, a second eptifibatide bolus 10 minutes after the initial dose further enhances platelet inhibition at 1 hour. Since both agents dissociate from the GP IIb/IIIa receptor rapidly, normal platelet aggregation is restored within 4 to 8 hours after drug discontinuation [33,34,35].

Platelet counts should be monitored within the first 24 hours while taking GP IIb/IIIa inhibitors. For abciximab, platelet counts should be evaluated within 2 to 4 hours of initiation due to a higher risk of thrombocytopenia.

GP IIb/IIIa inhibitors are included in evidence-based guidelines as adjunctive therapy for patients with ACS and those undergoing PCI (Table 110.5).

Optimal use of GP IIb/IIIa inhibitors involves appropriate patient risk stratification, use with other antithrombotic agents, appropriate dose, and duration of therapy [36].

The frequency of major bleeding with GP IIb/IIIa therapy ranges from 1% to 14% of patients and depends on the agent, concomitant therapies, and settings of ACS or PCI [32,33,34]. Failure to adjust dosing in renal dysfunction further increases the risk of bleeding [37]. Factors associated with bleeding risk include age, female gender, body weight, diabetes, congestive heart failure, renal function, concomitant fibrinolytic use, prolonged femoral sheath placement, and heparin dosing [38,39].

The duration of the antiplatelet effect is agent specific and is influenced by platelet binding (abciximab binds to platelets for up to 10 days) and renal function (tirofiban and eptifibatide have half-lives of 1.5 to 3 hours with normal renal function). An intravenous desmopressin dose of 0.3 μg per kg may be beneficial in reducing bleeding time [17].

Nonhemorrhagic side effects of GP IIb/IIIa inhibitors include severe thrombocytopenia. The incidence of thrombocytopenia with eptifibatide and tirofiban is similar to placebo, with rates ranging from 0.2% to 0.3% of treated patients. With abciximab, the incidence is reported as 5%; however, up to 4% of cases can be due to pseudothrombocytopenia as a result of platelet clumping. The onset of thrombocytopenia usually occurs within the first 24 hours of infusion, but delayed onset has been reported [40,41].

Platelet or red blood cell transfusions may be warranted for patients with persistent thrombocytopenia or clinically significant bleeding and must take into account drug concentrations in the plasma or drug bound to platelets [31]. Abciximab has been associated with antibody formation in 6% of patients. The risk of thrombocytopenia and immune-mediated reactions may limit repeat use [8,10,32]. GP IIb/IIIa inhibitor administration should be avoided in patients requiring neuraxial analgesia due to risk of subdural hematoma [30].

Dipyridamole inhibits adenosine binding to platelets and endothelial cells. The increase in adenosine leads to a rise in cyclic adenosine monophosphate (cAMP), which in turn decreases platelet responsiveness to various stimuli. Dipyridamole is
metabolized hepatically and has a half-life of approximately 10 hours [10].

Dipyridamole is indicated as adjunctive therapy for the prevention of thromboembolism in patients with cardiac valve replacement. Combined with aspirin, dipyridamole is indicated for secondary prevention of cerebrovascular accidents and TIA. The combination of aspirin and extended-release dipyridamole was associated with reductions in major vascular events in patients with stroke or TIA (Table 110.6) [10,42].

While headache is the most common adverse effect associated with dipyridamole therapy, hemorrhage may also occur. For patients exhibiting clinically significant bleeding, platelet transfusion may be warranted.

Cilostazol blocks platelet activation via phosphodiesterase 3 (PDE3) inhibition. PDE3 inhibition increases cAMP concentrations resulting in inhibition of platelet aggregation and an increase in vasodilation [43].

Cilostazol is extensively metabolized by CYP 450-3A4 subclass. Avoidance of therapy or reduced dosing may be required for patients taking potent CYP3A4 inhibitors [44].

Cilostazol is indicated for treatment of intermittent claudication symptoms and has shown benefit in reducing symptoms and improving walking distance [44].

Nonhemorrhagic complications of cilostazol therapy include headache, peripheral edema, and tachycardia [44].

UFH is composed of a heterogeneous mixture of highly sulfated polysaccharide chains that vary in molecular weight, anticoagulant activity, and pharmacokinetic properties. A minimum of 18 saccharide units are required for UFH to form a ternary complex with AT and inhibit thrombin. Once bound to AT molecules, UFH can readily dissociate and bind to other AT molecules. Alternatively, the only requirement for factor Xa inhibition is for the heparin-AT complex to be formed. Heparin has equal inhibitory activity against factor Xa and thrombin, binding in a 1:1 ratio.

Since UFH is poorly absorbed orally, intravenous or subcutaneous injections are the preferred administration routes [47]. When given as subcutaneous injection with therapeutic intent, UFH doses need to be large enough (> 30,000 units per day) to overcome erratic bioavailability. UFH readily binds to plasma proteins after parenteral administration which contributes to variable anticoagulant response. Despite these limitations, intravenous administration rapidly achieves therapeutic plasma concentrations that can be monitored and adjusted based on infusion rates [45].

UFH clearance from systemic circulation is dose related and occurs through two independent mechanisms [46,48]. The initial phase is rapid and saturable binding to endothelial cells, macrophages, and local proteins where UFH is depolymerized. The second phase is a slower, nonsaturable, renal-mediated clearance. At therapeutic doses, UFH is cleared primarily in the initial phase with higher-molecular-weight chains being cleared more rapidly than lower-weight counterparts. As elimination becomes dependent on renal clearance, increased or prolonged UFH dosing provides a disproportionate increase in both the intensity and duration of anticoagulant effect. With therapeutic intravenous doses of heparin, the half-life of UFH is approximately 60 minutes [46,48].

The anticoagulant response to UFH is monitored using activated partial thromboplastin time (aPTT), a measurement sensitive to the inhibitory effects of thrombin. The aPTT should be measured every 6 hours, and doses adjusted accordingly, until the patient sustains therapeutic levels. Once steady state is reached, the frequency of monitoring can be extended.

Weight-based dosing nomograms are recommended for treatment of thromboembolic disease. Such nomograms have been associated with a shorter time to reach a therapeutic level without an increase in bleeding events. Heparin dosing nomograms differ between hospitals due to differences in thromboplastin agents and interlaboratory standards in aPTT measurements [49].