Antithrombotic Pharmacotherapy



Antithrombotic Pharmacotherapy


Christopher D. Adams

Kevin E. Anger

Bonnie C. Greenwood

John Fanikos



Introduction

Thromboembolic disease is commonly encountered among critically ill patients [1]. While these patients are at high risk for developing arterial and venous thrombosis due to underlying comorbidities, central venous catheter placement, and immobility, they are also at high risk for hemorrhagic complications resulting from gastrointestinal stress ulcerations, invasive procedures, liver dysfunction, uremia, or coagulopathy [2]. These divergent features often complicate antithrombotic treatments for prevention or management of thrombosis. Limitations in administration routes, hemodynamic instability, alterations in renal and hepatic function, and drug interactions further complicate the administration of these high-risk medications [3].

This chapter focuses on the mechanism of action, pharmacokinetics, pharmacodynamics, clinical indications, complications of therapy, and reversal options for antithrombotic pharmacotherapy in critically ill patients.


Antiplatelet Pharmacotherapy


Overview of Antiplatelet Pharmacotherapy

Antiplatelet agents target mechanisms in platelet activation, adhesion, and aggregation. Pharmacological inhibitors of platelet function fall into four general categories: thromboxane (TXA) inhibitors, antagonists of adenosine diphosphate (ADP)-mediated platelet activation, glycoprotein (GP) IIb/IIIa inhibitors, and phosphodiesterase inhibitors (Fig. 110.1).

Antiplatelet “resistance” and “nonresponse” are terms applied to clinical outcomes characterized by failure to prevent a thrombotic event due to inadequate platelet inhibition [4]. Resistance is conferred by underlying clinical, cellular, and genetic mechanisms. It is best confirmed by platelet function testing [5]. While several methods are available for measuring overall and drug-specific platelet aggregation, standard testing protocols have yet to be established [6].


Aspirin and Aspirin Derivatives


Pharmacology, Pharmacodynamics, and Monitoring

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].






Figure 110.1. Platelet activation and pharmacological inhibitors of platelet function. Platelet activation involves four mechanisms: adhesion to sites of vascular injury, release of stimulatory compounds, aggregation, and priming of coagulation. Pharmacological inhibitors of platelet function target adhesion, release, and aggregation mechanisms. Platelet adhesion is a four-step process involving tethering of von Willebrand factor (VWF) to glycoprotein (GP) Ib platelet receptors, a potential target of investigational agents. The rolling phase of adhesion involves interaction between vascular collagen with GP VI and GP Ia/IIa receptors, another potential target of investigational agents. The activation phase of adhesion involves release of thromboxane A2 (TXA2) and adenosine diphosphate (ADP) which can be blocked with use of aspirin and P2Y12 inhibitors, respectively. The stable adhesion phase involves the interaction of GP IIb/IIIa receptors with fibrinogen and VWF, which can be blocked with the use of GP IIb/IIIa inhibitors.


Clinical Indications

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].


Complications and Reversal of Effect

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].








Table 110.1 Clinical Uses of Aspirin


































Drug Indications Dosing, timing, duration Precautions
Acetylsalicylic acid (aspirin) Treatment of acute coronary syndromes Load 162–325 mg orally Initial dosing for stents 162–325 mg orally/d:
Bare metal 1 mo
Sirolimus 3 mo
Paclitaxel 6 mo
Maintenance: 81–325 mg/d orally


  • Thrombocytopenia
  • Bleeding disorders
  • Pregnancy (third trimester)
  • Gastrointestinal disorders
  • Renal failure
  • Severe hepatic insufficiency
  • Concomitant antithrombotic medication use
  Primary and secondary prevention of myocardial infarction in patients with chronic stable angina, previous MI, or unstable angina 81–325 mg/d orally

  • Alcohol consumption
  Secondary prevention in stroke and TIA patients 75–325 mg/d orally  
  Acute thrombotic stroke 160–325 mg/d, initiated within 48 h (in patients who are not candidates for fibrinolytics and are not receiving systemic anticoagulation)  
  Secondary prevention in CABG, carotid endarterectomy patients 75–325 mg/d starting 6 h following procedure; if bleeding prevents administration at 6 h after CABG, initiate as soon as possible  
CABG, coronary artery bypass graft; MI, myocardial infarction; TIA, transient ischemic attack.


P2Y12 Inhibitors


Pharmacology, Pharmacodynamics, and Monitoring

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.


Clinical Indications

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].








Table 110.2 Pharmacokinetic and Pharmacodynamic Properties of P2Y12 Inhibitors












































































  Ticlopidine Clopidogrel Prasugrel Ticagrelora Cangrelora Elinogrela
Route Oral Oral Oral Oral IV Oral/IV
Receptor binding Irreversible Irreversible Irreversible Reversible Reversible Reversible
Prodrug Yes Yes Yes No No No
Metabolism CYP3A4 CYP3A4, 2B6 CYP3A4, 2B6, 2C9, 2C19 CYP3A4 Plasma esterase Not reported
Clearance Renal 60%
Fecal 23%
Renal 50% Fecal 46% Renal 68%
Fecal 27%
Renal 1% Renal 52% Fecal 48%
Time to peak platelet inhibition 2–5 d 300 mg LD: 6 h
600 mg LD: 2 h
1–2 h 2 h 30 min 20 min (IV)
Duration of antiplatelet effect 7–10 d 7–10 d 7–10 d 1 d 20–60 min 1 d
Genetic polymorphisms Yes Yes No No Not reported Not reported
aInvestigational agent.
IV, intravenous; CYP, cytochrome P; LD, loading dose.


Complications and Reversal of Effect

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.








Table 110.3 Clinical Uses of P2Y12 Inhibitors












































Drug Indications Dosing, timing, duration Precautions
Clopidogrel (Plavix™) Treatment of acute coronary syndromes +/- percutaneous intervention Load 300 mg ×1
PCI load: 300–600 mg ×
1 Maintenance 75 mg/d orally Drug-eluting stents: duration of clopidogrel ideally 12 mo following drug-eluting stent


  • Age > 75 y (prasugrel)
  • Interruption of clopidogrel may cause in-stent thrombosis with subsequent fatal and nonfatal myocardial infarction
  Primary and Secondary prevention of myocardial infarction in patients with chronic stable angina, previous MI, or unstable angina 75 mg orally once daily

  • Indwelling epidural catheter
  • Combination of aspirin and clopidogrel in patients with recent TIA or stroke
  Cerebrovascular accident  

  • Liver disease
  Arteriosclerotic vascular disease  

  • Thrombotic thrombocytopenic purpura may occur (rare)
  Peripheral arterial occlusive disease  

  • Recent trauma, surgery/biopsy
  • Hematologic disorders
Ticlopidine (Ticlid™) Placement of stent in coronary artery Secondary prevention in thromboembolic stroke 250 mg orally twice a day

  • Discontinue if ANC less than 1,200/μL or platelet count less than 80,000/μL (ticlopidine)
Prasugrel (Effient™) Treatment of acute coronary syndromes +/- percutaneous intervention Load 60 mg × 1 Maintenance: 10 mg/d orally Weight < 60 kg, consider using a lower maintenance dose of 5 mg/d

  • Elevated triglycerides (ticlopidine)
ANC, absolute neutrophil count; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.









Table 110.4 Pharmacokinetic and Pharmacodynamic Properties of Glycoprotein IIB/IIIA Inhibitors

















































  Abciximab Eptifibatide Tirofiban
Agent type Fab fragment of human–mouse chimeric monoclonal antibody Cyclic heptapeptide Nonpeptide
Antigenicity Yes No No
Receptor binding effect Reversible Reversible Reversible
Receptor affinity High Moderate Moderate
Excretion Renal and reticuloendothelial system 50% renal 39%–69% renal
Dosage reduction in renal failure No Yes, decrease infusion dose by 50% if CrCl < 50 mL/min Yes, decrease infusion dose by 50% if CrCl < 30 mL/min
Removable by dialysis No Yes Yes
Duration of antiplatelet effect 24–48 h 4–8 h 4–8 h
CrCl; creatinine clearance using Cockcroft–Gault equation.


Glycoprotein IIb/IIIa Inhibitors


Pharmacology, Pharmacodynamics, and Monitoring

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.


Clinical Indication

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].


Complications and Reversal of Effect

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


Pharmacology, Pharmacodynamics, and Monitoring

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].








Table 110.5 Clinical Uses of Glycoprotein IIB/IIIA Inhibitors





























Drug Indications Dosing, timing, duration Precautions
Eptifibatide (Integrilin™) Treatment of acute coronary syndromes +/- percutaneous coronary intervention IV bolus 180 μg/kg ABW (maximum 22.6 mg) as soon as possible, followed by 2 μg/kg ABW/min (maximum 15 mg/h) infusion until discharge or CABG surgery, up to 72 h If undergoing PCI, administer a second 180 μg/kg IV bolus 10 min after the first and continue the infusion up to discharge, or for up to 18–24 h after procedure, whichever comes first, allowing for up to 96 h of therapy

  • Concomitant use of fibrinolytics, anticoagulants, antiplatelet agents, and nonsteroidal anti-inflammatory agents
  • Indwelling epidural catheter
  • Do not remove arterial sheath unless aPTT is less than 45 s or ACT less than 150 s and heparin discontinued for 3–4h
    Renal adjustment
CrCl < 50 mL/min, 180 μg/kg actual body weight (maximum 22.6 mg) IV bolus as soon as possible, followed by 1 μg/kg/min (maximum 7.5 mg/h) infusion


  • Platelet count below 150,000/μL
  • Renal insufficiency (eptifibatide)
  • Severe renal insufficiency, chronic hemodialysis (tirofiban)
  • Readministration of abciximab may result in hypersensitivity, thrombocytopenia, or diminished benefit due to antibody formation
  • Hemorrhagic retinopathy
Abciximab (Reopro™) Treatment of acute coronary syndromes +/- percutaneous coronary intervention Initial, 0.25 mg/kg IV bolus (over 5 min), followed by 0.125 μg/kg/min (maximum 10 μg/min) IV infusion for 12 h in combination with fibrinolytic treatment or after PCI, unless complications
No adjustment required for renal dysfunction
 
Tirofiban (Aggrastat™) Treatment of acute coronary syndromes 0.4 μg/kg/min IV for 30 min, then 0.1 μg/kg/min for 12–24 h after PCI
Severe renal impairment (CrCl less than 30 mL/min): give half the usual dose–0.2 μg/kg/min IV for 30 min, then 0.05 μg/kg/min
 
ABW, actual body weight; ACT, activated clotting time; aPTT, activated thromboplastin time; CABG, coronary artery bypass graft; CrCl; creatinine clearance using Cockcroft–Gault equation; IV, intravenous; PCI, percutaneous coronary intervention.


Clinical Indications

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].


Complications and Reversal of Effect

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


Pharmacology, Pharmacodynamics, and Monitoring

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].


Clinical Indication

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


Complications and Reversal of Effect

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


Overview of Anticoagulant Pharmacotherapy

Blood coagulation has been summarized previously in Chapter 108. Anticoagulant agents inhibit thrombosis and propagation by inhibiting thrombin directly or indirectly by attenuating thrombin generation (Fig. 110.2). Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are effective in acute thrombosis due to their rapid onset. Since heparins are dependent on the presence of antithrombin (AT) for clotting factor inhibition, they are considered indirect anticoagulants. Heparins contain a pentasaccharide sequence that binds to AT, producing a conformational change that accelerates AT inactivation of coagulation factors XIIa, IXa, XIa, Xa, and IIa (thrombin). Of these, thrombin and Xa play the most critical role in the coagulation cascade. The active pentasaccharide sequence responsible for catalyzing AT is found on one-third and one-fifth of the chains of heparin and LMWH, respectively. Fondaparinux is a synthetic analog of this naturally occurring pentasaccharide [45,46,47].









Table 110.6 Clinical Uses of Phosphodiesterase Inhibitors
























Drug Indications Dosing, timing, duration Precautions
Dipyridamole (Persantine™) Radionuclide myocardial perfusion study VTE prophylaxis after heart valve replacement 0.142 mg/kg/min IV for 4 min (0.57 mg/kg total) prior to thallium; maximum 60 mg With concomitant warfarin therapy: 75–100 mg orally four times daily

  • Aminophylline injection should be readily available for relieving adverse effects such as chest pain and bronchospasm
  • Hypotension
  • Severe coronary artery disease, abnormal cardiac rhythm
Dipyridamole extended-release/aspirin (Aggrenox™) Secondary prevention in stroke and TIA patients 200 mg dipyridamole, 25 mg aspirin (1 capsule) orally twice daily Patients with intolerable headache 200 mg dipyridamole, 25 mg aspirin orally daily at bedtime, with 81 mg of aspirin in the morning Return to usual dose as soon as tolerance to headache develops (usually within a week)

  • Avoid in patients with severe hepatic insufficiency
  • Avoid in patients with severe renal failure (CrCl less than 10 mL/min)
  • Severe coronary artery disease
  • Coagulation abnormalities
  • Severe renal impairment
Cilostazol (Pletal™) Intermittent claudication 100 mg orally twice a day  
CrCl, creatinine clearance using Cockcroft–Gault equation; IV, intravenous; TIA, transient ischemic attack; VTE, venous thromboembolism.


Unfractionated Heparin


Pharmacology, Pharmacodynamics, and Monitoring

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].

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Sep 5, 2016 | Posted by in CRITICAL CARE | Comments Off on Antithrombotic Pharmacotherapy
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