Agents That Act on Blood

Chapter 25


Agents That Act on Blood


Theresa Pluth Yeo and Susan E. Shirato






INDICATIONS




• Prevention or treatment of venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary emboli (PE); arterial ischemic events such as ischemic stroke and TIAs, acute MI, and intermittent atrial fibrillation (AF); and prevention and treatment of peripheral arterial thrombosis. See Table 25-1 for indications for specific drugs.



TABLE 25-1


Indications/Uses for Drugs That Act on Blood











































































Category Drug Indications/Uses
Heparin group Heparin Prevention of VTE in patients undergoing major abdominothoracic surgery or who for other reasons are at risk of developing thromboembolic disease; prophylaxis and treatment of pulmonary embolism and atrial fibrillation with embolization, for diagnosis and treatment of acute and chronic DIC, for prevention of clotting in arterial and heart surgery, for prophylaxis and treatment of peripheral arterial embolism, and as an anticoagulant in blood transfusions, extracorporeal circulation, and dialysis procedures. Not recommended for treatment of acute ischemic stroke
  LMWH, fondaparinux Prevention of VTE in patients undergoing major abdominothoracic and orthopedic surgery and in medically ill patients; treatment of pulmonary embolism and acute coronary syndrome; bridge therapy for anticoagulated patients preoperatively and in postpercutaneous intervention; for revascularization therapy; and in patients discharged on recently initiated warfarin with a subtherapeutic INR
Oral anticoagulants warfarin Venous thromboembolism, high-risk surgery, prophylaxis (abdominal and orthopedic surgery); short-term treatment of single episode of DVT or PE (3-6 mo); prevention of VTE; indefinite treatment for recurrent DVT or PE; prevention of systemic embolism; postmechanical prosthetic heart valve replacement, cardiomyopathy, or acute MI (3 mo); and AC cardioversion in atrial fibrillation, tissue cardiac valve replacement (3 mo), atrial fibrillation, valvular heart disease, mechanical prosthetic heart valves
  dabigatran Prevent blood clots from forming because of a certain irregular heart rhythm (atrial fibrillation). Preventing these blood clots helps to reduce the risk of a stroke. Pradaxa is an anticoagulant that works by blocking a certain substance (a type of clotting protein called thrombin) in your blood.
PLATELET INHIBITORS
Traditional aspirin MI (treatment and prophylaxis); stroke, acute ischemic; thromboembolism (prophylaxis in select cases)
  dipyridamole Adjunctive therapy with warfarin in prevention of postoperative thromboembolic complications in cardiac valve replacement; plays no helpful role when used alone for ischemic stroke or TIA
ADP-induced inhibitors clopidogrel Recent MI or stroke; established peripheral arterial disease; to reduce risk of new stroke, acute coronary syndrome, MI
  ticlopidine Prevention of thrombotic stroke, coronary stenting
  prasugrel Prevention of myocardial infarction, strokes, and cardiovascular-related deaths (due to myocardial infarctions or strokes) in people who have had an angioplasty procedure to treat a coronary artery occlusion after experiencing a myocardial infarction or heart-related chest pain. It is used in combination with aspirin.
GPIIb/IIIa inhibitors abciximab Angioplasty; patients with unstable angina not responding to conventional medical therapy and for whom percutaneous coronary intervention is planned within 24 hours
  eptifibatide Angioplasty, adjunct; acute coronary syndrome
  tirofiban Acute coronary syndrome
PDEIII inhibitors anagrelide Thrombocythemia, thrombocythemia secondary to myeloproliferation
  cilostazol Intermittent claudication
Thrombolytic agents Varies with specific drug MI, acute ischemic stroke, PE, DVT, peripheral arterial occlusion
Hemorheologic agents pentoxifylline Intermittent claudication (rarely used)


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Anticoagulant drugs prolong the body’s ability to form a thrombus (clot) at various points in the coagulation cascade. The goal of therapy is to promote anticoagulation while minimizing hemorrhagic complications through careful monitoring. These medications must be used with great care and often under the supervision of a specialist.


The list of drugs discussed in this chapter is detailed to give the names the provider may recognize. However, only those drugs used in primary care will be discussed in detail. LMWH is more commonly seen now in primary care, although unfractionated heparin (UFH) is still in use. Warfarin, dabigatran, clopidogrel, and aspirin (ASA) are probably the most important drugs in this chapter for the primary care provider. The provider must have a complete understanding of the mechanism of action, dosing, monitoring, and side effects of these drugs in order to prescribe them. The first two groups of platelet inhibitors are seen in primary care. The newer platelet inhibitors remain specialty medications. Thrombolytics and direct thrombin inhibitors (DTIs) are used only in the acute care setting and are included here for those times when the primary provider has contact with patients who are experiencing acute cardiovascular events. Providers need to be aware of the time constraints surrounding initiation of thrombolytic therapy if they are to make timely transfers and referrals to tertiary care centers. The hemorheologic agent is also discussed briefly here. The newest direct thrombin inhibitor, dabigatran (Pradaxa), is discussed in detail.



Therapeutic Overview


Anatomy and Physiology


A delicate balance must be maintained between the fluidity of the bloodstream and the ability of blood to clot quickly to prevent hemorrhage. In the coagulation system, two pathways are necessary for clotting. The intrinsic clotting pathway is initiated when the blood is exposed to a negatively charged surface such as the in vitro coagulation activators celite, kaolin, or silica. The intrinsic pathway is triggered when blood comes into contact with damaged endothelium or collagen. The extrinsic clotting pathway is triggered by exposure of tissue factor at the site of tissue injury or the addition of thromboplastin to blood. The intrinsic and extrinsic pathways merge on the activation of factor X in what is referred to as the final common pathway (Figure 25-1). Factor X then converts factor II (prothrombin) to IIa (thrombin), and factor IIa converts fibrinogen to a fibrin clot (thrombus).


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FIGURE 25-1 Coagulation and fibrinogen systems.
Site of action of antithrombotic and thrombolytic drugs.

Platelets provide the initial response to tissue injury (bleeding) and are activated by thrombin, ADP, serotonin, and epinephrine. They next adhere to collagen or to the damaged endothelium and then aggregate to form a platelet plug on the damaged cell wall. During this time, platelets also trigger formation of the active clotting factors VII and X, which leads to clot formation. The fibrin-bound clot framework itself stimulates activation of additional platelets. These platelets release thromboxane A2, serotonin, and ADP, which enhance platelet aggregation and reinforce the formed clot.


Studies suggest that flavonoids found in fruits, vegetables, and some beverages such as tea, coffee, beer, and fruit drinks inhibit several measures of platelet activity such as epinephrine- and ADP-induced GPIIb/IIIa and P-selection expression.



Pathophysiology


The normally protective mechanism can become destructive to the body and can serve as the source of further pathology when clots form in certain areas and prevent tissues from receiving blood. Tissue ischemia and necrosis occur distal to the arterial thrombosis and manifest as MI, stroke, and acute peripheral arterial occlusion. Venous thrombi can result in PE.


A number of acquired factors are associated with increased risk for a thromboembolic event (Box 25-1). Most of these factors are linked to decreased circulation, reduced mobility, or obstruction of blood flow. Many are the result of other diseases or disability or disabilities. One of the critical decisions that a clinician must make is whether it is possible to reduce or control risk factors in order to minimize the chance of thromboembolic events. Clinicians should suspect inherited risk factors, such as deficiency of anticoagulation proteins C and S, antithrombin III deficiency, factor V Leiden mutation, prothrombin G20210A mutation, and factor VIII elevations in patients displaying unusual procoagulable or prothrombotic tendencies. Hyperhomocysteinemia is found in about 5% of the population and is associated with a threefold increase in VTE. Virchow’s triad describes inherited and acquired conditions that place patients at increased risk for developing emboli; these include hypercoagulable states, endothelial injury, and circulatory stasis.



BOX 25-1   Acquired Risk Factors for Thromboembolic Events





Disease Process


Most of these drugs are used to prevent or treat blood clots that cause thromboembolic events such as stroke, MI, DVT, and PE. The most important pathogenic mechanism in angina and MI is an intracoronary, platelet-rich thrombus on a disrupted, ulcerated, or eroded atherosclerotic plaque leading to partial or complete coronary artery occlusion. The same process occurs in the internal carotid artery or the atria of the heart, and this leads to a stroke. Venous stasis frequently gives rise to clot formation or DVT. If this thrombus dislodges or embolizes, it then causes a PE. PE is the leading cause of preventable hospital death in the United States.


Most cases of chronic peripheral arterial occlusive disease are caused by atherosclerosis. The femoropopliteal, tibioperoneal, aortoiliac, carotid, vertebral, splanchnic, renal, and brachiocephalic arteries are most commonly involved. In chronic arterial occlusive disease, the goals of antithrombotic drug therapy are to relieve symptoms of pain and claudication and to prevent progression of disease that may lead to loss of the limb.




Mechanism of Action


Heparin


Heparin has no effect on existing clots; it prevents or retards formation of new thrombi. Heparin acts at multiple sites in the coagulation system and binds with antithrombin III (AT-III) at two specific sites, resulting in its anticoagulant effect. At the first heparin–AT-III binding site, factor Xa is neutralized, thereby exerting a direct effect on factor X. Factor X is responsible for initiating the final common pathway in the clotting cascade (see Figure 25-1), which ends in clot formation. The second heparin–AT-III binding occurs at the site of conversion of prothrombin to thrombin (factor IIa). With decreased thrombin available, a reduced amount of fibrin is made from fibrinogen. Standard UFH is a mixture of polysaccharide molecules that vary in average molecular weight and composition. Typically, only one third of the molecules in a standard UFH preparation contain the pentasaccharide sequence needed for antithrombin binding and anticoagulation.


Low molecular weight heparin (LMWH) has several advantages over UFH. It has a more predictable anticoagulant effect along with a higher ratio of anti–factor Xa to anti–factor IIa, thus inhibiting the generation of thrombi higher in the clotting cascade. A characteristic of LMWH is that it cannot be monitored with an aPTT as heparin can. Use of LMWH results in a lower incidence of heparin-induced thrombocytopenia and possibly in lower risks of bleeding and osteopenia.



Oral Anticoagulants


Warfarin competitively blocks vitamin K–binding sites and inhibits the synthesis of vitamin K–dependent coagulation factors VII, IX, X, and II (prothrombin) and anticoagulant proteins C and S. Warfarin and anisindione (rarely used) are often referred to as vitamin K antagonists (VKA). At therapeutic levels, warfarin decreases liver synthesis of vitamin K–dependent clotting factors by 30% to 50%. These clotting factors have different half-lives. Factor VII has the shortest half-life (6-9 hr) vs. factors II and X (up to 72 hr). Oral anticoagulants do not reverse ischemic damage or lyse an established thrombus but rather prevent extension of the existing thrombus and the formation of new thrombi by blocking synthesis of clotting factors. Existing clotting factors are not affected; therefore, the onset of action of warfarin is dependent on when existing factors are inactive. This can take several days and should be monitored closely.


It is critical to understand these vitamin K–dependent clotting factors and their half-lives if warfarin is being prescribed. Warfarin is the number one drug causing adverse drug effects in hospitals, sometimes because clinicians do not understand these times. The activity of various clotting proteins (logarithmic scale) is shown in Table 25-2 as a function of time after ingestion of warfarin (10 mg/day po for 4 consecutive days) by a normal subject. Factor VII activity, to which prothrombin time is most sensitive, is the first to decrease. Full anticoagulation, however, does not occur until factors IX and X and prothrombin are sufficiently reduced. Protein C activity falls quickly, and, in some patients, a transient hypercoagulable state may ensue (e.g., coumarin necrosis) (Furie, 2000).



Pradaxa is a new oral anticoagulant, a first-in-class direct thrombin inhibitor. It blocks the activity of thrombin and helps to prevent clot formation. An estimated 2.3 million Americans have atrial fibrillation (AF), and the prevalence is expected to increase 2.5-fold to 5.6 million by 2050, reflecting the growing population of elderly individuals. Approval of Pradaxa was based on the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) trial. This multicenter, multinational, randomized parallel group trial compared Pradaxa (110 mg twice daily and 150 mg twice daily) with open-label warfarin (dosed to target INR of 2 to 3) in patients with nonvalvular, persistent, paroxysmal, or permanent AF with ≥1 risk factors. The primary end point was noninferiority to warfarin in reducing the occurrence of the composite end point, stroke (ischemic and hemorrhagic), and systemic embolism.


A total of 18,113 patients were randomized and followed for a median of 2 years. Pradaxa 150 mg twice daily significantly reduced the primary composite end point of stroke and systemic embolism, as compared with the 110 mg twice daily dose and warfarin. Pradaxa capsules are oral capsules given twice daily and are available in two dosage strengths: 75 mg (for reduced renal function) and 150 mg (for nonrenal compromised patients). There are no requirements for monitoring the INR or other measures for patients taking Pradaxa. When changing from warfarin, it is recommended that Pradaxa be initiated when the INR <2. Pradaxa is the first new oral anticoagulant to be FDA approved in over 50 years. It will compete heavily with warfarin because no INR monitoring is required. However, serious safety concerns exist with Pradaxa because it has a higher risk of GI bleeding in addition to an increased cost.



Platelet Aggregation Inhibitors


Aspirin (ASA) prevents platelet aggregation by inhibiting cyclooxygenase in platelets and endothelial cells, thereby preventing the synthesis of thromboxane A2 and prostacyclin, both of which are potent platelet aggregators and vasoconstrictors.


Dipyridamole increases the body’s adenosine levels, producing vasodilation, particularly of the coronary arteries, which improves blood flow. It also inhibits phosphodiesterase, the enzyme responsible for elevating levels of cyclic adenosine monophosphate (cAMP). Low levels of cAMP are associated with reduced platelet adhesiveness.


Clopidogrel (Plavix) inhibits platelet aggregation by inhibiting the binding of ADP to its platelet receptor and the subsequent ADP-mediated activation of the GPIIb/IIIa complex. The effect is irreversible; platelets exposed to clopidogrel are affected for the remainder of their life span (about 10 days). Ticlopidine inhibits platelet aggregation by altering the function of the platelet membrane to inhibit ADP-induced platelet-fibrinogen binding. The antiplatelet agent prasugrel was approved by the FDA on July 10, 2009. Like clopidogrel and ticlopidine, prasugrel is a platelet inhibitor of the thienopyridine class. All drugs in this class act as ADP receptor antagonists. What makes these drugs unique is their safety profile and pharmacokinetic properties. Although clopidogrel is a widely prescribed agent, it has limitations such as a modest antiplatelet effect, delayed onset of action, and considerable interpatient variability in drug response. All these disadvantages motivated the development of more effective and predictable agents, such as the novel prasugrel. Much controversy has surrounded the approval of prasugrel.


It is uncertain what role this drug will play in the prevention of MI, as well as the optimal dosing and adverse effects profile. Prasugrel is a pro-drug; oxidation by intestinal and hepatic cytochrome P-450 enzymes converts prasugrel into its active metabolite. Prasugrel is rapidly and almost completely absorbed after oral ingestion of a loading dose. Its active form binds irreversibly to the adenosine diphosphate (ADP) P2Y12 receptor on platelets for their life span, thereby inhibiting their activation and decreasing subsequent platelet aggregation. Prasugrel has a greater antiplatelet effect than clopidogrel because it is metabolized more efficiently. Some of the differences in metabolism between clopidogrel and prasugrel may be explained by genetic polymorphisms affecting the cytochrome P-450 system. Prasugrel coadministrated with aspirin is approved by the European Commission for the prevention of atherothrombotic events in patients with acute coronary syndromes (e.g., unstable angina, non-ST segment elevation myocardial infarction, or ST segment elevation myocardial infarction) undergoing primary or delayed percutaneous coronary intervention (PCI). Prasugrel includes a “black box” warning alerting prescribers that the drug can cause significant, and sometimes fatal, bleeding. The drug should not be used in patients with active pathologic bleeding, a history of TIAs (transient ischemic attacks) or stroke, or urgent need for surgery, including coronary artery bypass graft surgery.


Parenteral GPIIb/IIIa inhibitors are used to decrease the rate of ischemic events during balloon angioplasty and to improve coronary patency before stenting. The GPIIb/IIIa receptors are exposed immediately prior to aggregation that allows platelet-to-platelet attachment. This process also requires fibrinogen. The GPIIb/IIIa inhibitor drugs therefore block the binding sites, thereby inhibiting platelet aggregation. These drugs are approved for intravenous use in patients with acute coronary syndrome (ACS) and to prevent restenosis post–percutaneous transluminal coronary angioplasty (PTCA).


Anagrelide (Agrylin) has a mechanism of action that exerts a thrombocytopenic effect and also inhibits platelet aggregation. The thrombocytopenic effect appears to be a result of inhibiting megakaryocyte development in the late, postmitotic stage. In vitro, anagrelide altered maturation stage, size, and ploidy of developing megakaryocytes. Anagrelide does not appear to alter megakaryocyte progenitor cells or mitotic expansion of developing megakaryocyte precursors. The thrombocytopenic effects of anagrelide appear to be specific for humans. Clinically, anagrelide lowers platelet counts and reduces thrombosis, as well as thrombo-hemorrhagic symptoms associated with thrombocythemia.


At dosages higher than those required to produce thrombocytopenia in humans, anagrelide affects platelet aggregation. The drug inhibits platelet aggregation by inhibiting cyclic nucleotide phosphodiesterase and the release of arachidonic acid from phospholipase, possibly by inhibiting phospholipase A2. These actions increase platelet concentrations of cyclic adenosine monophosphate (cAMP). Anagrelide also inhibits collagen-induced platelet aggregation. Resistance to the drug effect does not appear to occur. Anagrelide does not produce significant changes in red cell or white cell counts or in coagulation parameters.


Cilostazol (Pletal) is a quinolone derivative that inhibits PDE3. The pharmacologic effects of cilostazol are multifactorial and include antithrombotic, antiplatelet, and vasodilatory actions. The actions of cilostazol with respect to peripheral arterial disease (PAD) may be particularly significant within the microcirculation. Cilostazol inhibits platelet aggregation caused by ADP, arachidonic acid, collagen, epinephrine, thrombin, and shear stress; it is 10 to 30 times more potent than aspirin in this regard, but cilostazol does not inhibit prostaglandin I2 synthesis. Cilostazol and its metabolites reversibly inhibit platelet aggregation via inhibition of phosphodiesterase (PDE) type 3 activity. This action suppresses degradation of cyclic AMP and increases levels of cyclic AMP in platelets. Cyclic AMP levels are also increased in the vascular tissue, promoting vasodilation. The vasodilatory actions of cilostazol are greater on femoral arteries than on vertebral, carotid, or superior mesenteric arteries. Renal arteries do not vasodilate in response to cilostazol administration.





Treatment Principles


Standardized Guidelines




• The eighth edition of Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians (ACCP) Evidence-Based Clinical Practice Guidelines and the 2010 Guidelines for Prevention of Stroke in Patients with Ischemic or Transient Ischemic Attack from the Stroke Council of the American Heart Association statement on primary prevention of stroke have provided important new information on the management and prevention of thromboembolic disorders, bridging therapy for those on anticoagulants during an invasive procedure, acute coronary syndromes, and ischemic stroke. Although prevention of ischemic stroke is the primary outcome of interest, the guidelines also identify strategies for the reduction of all vascular outcomes after stroke or TIA, including subsequent stroke, myocardial infarction (MI), and vascular death.





Nonpharmacologic and Pharmacologic Treatment


Prevention of VTE


The ACCP recommends against the use of ASA alone for prophylaxis of VTE. Patients undergoing surgery who are considered to be at moderate to high risk for VTE should receive UFH or LMWH. The use of graduated compression stockings and mechanical methods of thromboprophylaxis, such as intermittent pneumatic compression devices, should be added to the regimen for patients with multiple risk factors for VTE. In addition, all trauma patients with a minimum of one risk factor for VTE, patients admitted to an intensive care unit, those admitted to hospital with CHF or severe respiratory disease, and those who are immobile should receive routine thromboprophylaxis with LMWH and mechanical methods. Patients with confirmed, nonmassive PE are treated with intravenous UFH or subcutaneous LMWH. Patients with biosynthetic valves should receive anticoagulation for 3 months (INR goal, 2 to 3). Long-term prophylaxis for these patients should include ASA (75-100 mg daily), unless AF is present. Patients with ball or caged disk prosthetic heart valves require lifelong anticoagulation (INR goal, 2.5 to 3.5) provided in combination with ASA 75 to 100 mg daily.





Prevention of Stroke in Patients with Ischemic or Transient Ischemic Attack


The ACCP and The American Stroke Association Council on Stroke recognize that patients with a history of cardiac and/or cerebral vascular disease have an increased risk of recurrent stroke. Those with high-risk sources of cardiogenic embolism such as AF, chronic or paroxysmal, should be anticoagulated. In addition, systemic embolism or stroke occurs in approximately 12% of acute MI patients, particularly when complicated by left ventricular thrombus. ASA and VKA anticoagulation is recommended for this group.




Treatment of Acute Ischemic Stroke


For selected patients experiencing acute ischemic stroke (i.e., meeting the NINDS trial criteria), IV recombinant tissue plasminogen activator (e.g., rtPA, alteplase) should be initiated as quickly as possible; within 3 hours of symptom onset is recommended. The recommended dose of IV rtPA is 0.9 mg/kg, with maximum dose of 90 mg. This recommendation has not changed from previous recommendations. Alteplase is contraindicated if onset of symptoms occurred 3 hours previously. Patients not receiving thrombolytics should receive early ASA therapy (150-325 mg daily). The use of streptokinase or full-dose anticoagulation with IV or SQ UFH or heparinoids in acute ischemic stroke is discouraged, as it is associated with an increased risk of bleeding complications. Currently, the administration of anticoagulation or antiplatelet agents during the first 24 hours after treatment with IV rtPA for acute ischemic stroke is contraindicated. The oral administration of aspirin (325 mg) within 24 to 48 hours after stroke onset is recommended, and a small but significant decrease in mortality and mortality has been demonstrated. Although the combination of clopidogrel and aspirin is indicated in acute coronary syndromes, this combination has not been studied in acute ischemic stroke and is not recommended. In patients who have had a cardioembolic stroke caused by nonvalvular AF, heparin anticoagulation as primary therapy does not reduce the end points of death and disability.


In patients with extracranial or vertebral atherosclerosis who had an ischemic stroke or TIA, treatment with aspirin alone (75-325 mg), clopidogrel (75 mg daily), or the combination of aspirin or extended release dipyridamole (25 mg and 200 mg twice daily, respectively) is recommended.



Treatment of AF and Prevention of Stroke in AF


Persistent and paroxysmal AF is a predictor of first stroke and recurrent stroke risk. Those with persistent or paroxysmal AF and prior ischemic stroke, TIA, systemic embolism, or aged ≥75 years benefit from warfarin anticoagulation at an INR goal of 2.5 (range 2.0 to 3.0). For AF patients with more than one moderate risk factor (e.g., aged 75 years, hypertension, impaired LV function, ejection fraction 35%, or diabetes mellitus), warfarin anticoagulation is recommended. For patients unable to take VKAs, aspirin alone is recommended. The use of clopidogrel plus aspirin is not recommended due to risk of hemorrhage. The evidence supporting the efficacy of ASA is weaker than it is for warfarin. The Stroke Prevention in Atrial Fibrillation Trial used ASA at a dose of 325 mg daily. However, the results of the trial indicate the best efficacy and safety profile at a dose of 75 to 100 mg daily. When mitral stenosis is present or a prosthetic valve is in place, warfarin is indicated. The INR should be maintained at 2.5 for those with rheumatic valve disease (range 2.0 to 3.0) and INR of 3.0 (range 2.5 to 3.5) for mechanical prosthetic valves. ASA may be added to the regimen. Warfarin therapy of 3 to 4 weeks’ duration is recommended before electrical cardioversion of new onset AF (48 hours) is attempted. If onset of AF has occurred within 48 hours, cardioversion can be done without anticoagulation. In patients with rheumatic mitral valve disease and AF or a history of systemic embolism, anticoagulation plus ASA (75-100 mg daily) is indicated. If unable to tolerate ASA, clopidogrel is used. For patients with mitral valve prolapse (MVP), but without a history of systemic embolism or TIA, antithrombotic therapy is not recommended. If these conditions coexist with MVP, ASA (75-100 mg daily) is suggested.



Antithrombotic Treatment for ACS


Patients with non–ST-segment elevation (NSTE) ACS should receive ASA 162 to 325 mg po (chewed) immediately. When patients with ACS continue to exhibit symptoms after 1 hour of conventional therapy, abciximab or eptifibatide should be started. In patients who will not undergo diagnostic cardiac catheterization within 5 days of the event, bolus clopidogrel (300 mg) is recommended, followed by 75 mg daily for 9 to 12 months, in addition to ASA. If angiography is performed immediately, clopidogrel 300 mg should be given 6 hours prior to the procedure if possible. In patients considered at moderate to high risk for future events, eptifibatide or tirofiban therapy is encouraged, in addition to ASA and heparin.


Aspirin (81-162 mg daily) is recommended for all patients with coronary artery disease. Clopidogrel (75 mg daily) is used as an alternative for those few patients unable to take aspirin. Warfarin should not be given with clopidogrel and ASA concurrently.






Heparin


UFH is administered as a continuous intravenous infusion on an inpatient basis. For the prevention of VTE, a dose of 5000 units is given every 8 or 12 hours postoperatively. For the treatment of patients with VTE or ACS, a loading dose of ≈80 units/kg is followed by an infusion of 9 to 18 units/kg/hr, depending on the institution. Begin to monitor aPTT ≈3 to 4 hours after initiation so that any necessary adjustments to the dosage can be made. Generally, treatment is discontinued when the patient is past the risk of thromboembolic complications, but this varies with the specific indication. UFH is most often administered intravenously for 5 to 10 days. If indicated, oral anticoagulation with warfarin is given in conjunction (overlapping) with the heparin infusion because the maximal therapeutic effect of warfarin is not fully reached until after 4 to 5 days (Figure 25-2). Heparin resistance is seen in febrile patients and in those with active thrombosis, phlebitis, infection, MI, cancer, or heparin-induced thrombocytopenia (HIT). Concern has arisen about the possibility of increasing the risk of osteoporosis with prolonged standard heparin administration (>3 months, at an accumulated dose of 20,000 units).


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FIGURE 25-2 Algorithm for heparin administration decisions.
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Jul 22, 2016 | Posted by in PHARMACY | Comments Off on Agents That Act on Blood

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