With contraindications lo warfarin

FIGURE 10-5. Treatment approach for patients with VTE. (INR, International Normalized Ratio; IV, intravenous; LMWH, low-molecular weight heparin; PO, oral; SC, subcutaneous; UFH, unfrac-tionated heparin; VTE, venous thromboembolism.) (From Ref. 24.)

Table 10-3 Pharmacologic Options for the Initial Treatment of Acute VTE UFH

IV administration:a use weight-based dosing nomogram (Table 10-5)

SC administration: 17,500 units (250 units/kg) given every 12 hours (an initial 5,000 unit IV bolus dose is recommended to obtain rapid anticoagulation)

Adjust subsequent doses to attain a goal aPTT based on the institution-specific therapeutic range

SC administration: 333 units/kg followed by 250 units/kg given every 12 hours (fixed-dose un-monitored dosing regimen)

LMWHs

Dalteparin: 200 units/kg SC once daily or 100 units/kg SC twice dailyb

Enoxaparin: 1.5 mg/kg SC once daily or 1 mg/kg SC twice daily; if CrCl is less than 30 mL/min: 1 mg/kg SC once daily

Tinzaparin: 175 units/kg SC once daily or or

Factor Xa Inhibitor

Fondaparinux:

For body weight less than 50 kg (110 lb), use 5 mg SC once daily For body weight 50-100 kg (110-220 lb), use 7.5 mg SC once daily For body weight greater than 100 kg (220 lb), use 10 mg SC once daily aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; SC, subcutaneous; VTE, venous thromboembolism; UFH, unfractionated heparin; LMWHs, low-molecular weight heparins.

aIV administration preferred due to improved dosing precision.

bNot FDA-approved for treatment of VTE in noncancer patients.

In patients with acute PE, the use of thrombolytics provides short-term benefits such as restoring pulmonary artery patency and hemodynamic stability.17,26 A recent meta-analysis of nine small randomized clinical trials showed a slightly lower risk of death or recurrent PE in patients treated with thrombolytics when compared to those treated with heparin alone. However, this small benefit was offset by a higher risk 27

of major bleeding. Streptokinase, urokinase, and tissue plasminogen activator (t-

PA) have all been studied and are FDA-approved in the treatment of PE. All three agents have comparable thrombolytic capacity but t-PA has the potential advantage of a shorter infusion time. Reteplase is not currently FDA-approved for the treatment of

PE, but it has also been studied. Reteplase is administered as two 10 unit IV boluses

17,28

given 30 minutes apart. ' Given the relative lack of data to support their routine use, thrombolytics should be reserved for select high-risk circumstances (Table 10-4).

Candidates for thrombolytic therapy are patients with acute massive embolism who are hemodynamically unstable (systolic blood pressure [SBP] less than 90 mm Hg)

and at low risk for bleeding. The use of thrombolytics in hemodynamically stable patients with right ventricular dysfunction is controversial but some experts support their use.

Table 10-4 Thrombolysis for the Treatment of VTE

• Thrombolytic therapy should be reserved for patients who present with shock, hypotension, right ventricular strain, or massive DVT with limb gangrene

• Diagnosis must be objectively confirmed before initiating thrombolytic therapy

• Thrombolytic therapy is most effective when administered as soon as possible after PE diagnosis, but benefit may extend up to 14 days after symptom onset

• Approved PE thrombolytic regimens:

• Streptokinase 250,000 units IV over 30 minutes followed by 100,000 units/h for 24 hoursa

• Urokinase 4,400 units/kg IV over 10 minutes followed by 4,400 units/kg/h for 12-24 hoursa

• Alteplase 100 mg IV over 2 hours

• Factors that increase the risk of bleeding must be evaluated before thrombolytic therapy is initiated (i.e., recent surgery, trauma or internal bleeding, uncontrolled hypertension, recent stroke, or ICH)

• Baseline labs should include CBC and blood typing in case transfusion is needed

• UFH should not be used during thrombolytic therapy. Neither the aPTT nor any other anticoagulation parameter should be monitored during the thrombolytic infusion

• aPTT should be measured following the completion of thrombolytic therapy:

• If aPTT less than 2.5 times the control value, UFH infusion should be started and adjusted to maintain aPTT in therapeutic range

• If aPTT greater than 2.5 times the control value, remeasure every 2-4 hours and start UFH infusion when aPTT is less than 2.5

• Avoid phlebotomy, arterial puncture, and other invasive procedures during thrombolytic therapy to minimize the risk of bleeding aPTT, activated partial thromboplastin time; DVT, deep vein thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin; VTE, venous thromboembolism.

aTwo-hour infusions of streptokinase and urokinase are as effective and safe as alteplase. Unfractionated Heparin

UFH has traditionally been the drug of choice for indications requiring a rapid anticoagula-tion including the acute treatment of VTE. Commercially available UFH preparations are derived from porcine intestinal mucosa or bovine lung. UFH is composed of a heterogeneous mixture of glycosaminoglycans with variable length, molecular weight, and pharmacologic properties. Unlike thrombolytics, UFH and other anticoagulants will not dissolve a formed clot but prevent its propagation and

4 29

growth. ' Heparin exerts its anticoagulant effect by augmenting the natural anticoagulant, AT. A specific pentasaccharide sequence on the heparin molecule binds to AT and causes a conformational change that greatly accelerates its activity (Fig. 10-6). This complex inhibits thrombin (factor IIa), as well as factors Xa, IXa, XIa, and Xlla. Thrombin and factor Xa are most sensitive to this inhibition and are inactivated in an equal 1:1 ratio. In order to inactivate thrombin, the UFH molecule needs to form a ternary complex by binding to both AT and thrombin. Only UFH molecules that are at least 18 saccharide units long are able to form this bridge between AT and thrombin. In contrast, inhibition of factor Xa does not require the formation of a ternary complex. UFH molecules as short as five saccharide units can catalyze the inactivation of factor Xa. Due to its nonspecific binding to cellular proteins, UFH has several limitations, including poor bioavail-ability when given SC and significant intra-and interpatient variability in anticoagulant response.4,29

UFH can be administered via the IV or SC route.4 When rapid anticoagulation is required, UFH should be administered IV and an initial bolus dose should be given. For the treatment of VTE, UFH is generally given as a continuous IV infusion. Intermittent IV bolus dosing is associated with a higher risk of bleeding and is therefore not recommended. When given SC, the bio availability of UFH ranges from 30% to 70%, depending on the dose given. Therefore, higher doses of UFH must be given if the SC route of administration is used. Onset of anticoagulation is delayed by 1 to 2 hours after the SC injection. Due to the risk of hematomas and erratic absorption, intramuscular (IM) administration is not recommended. The half-life of UFH is dose dependent and ranges from 30 to 90 minutes, but maybe significantly longer, up to 150 minutes, with high doses. UFH is eliminated by two mechanisms: (a) enzymatic degradation via a saturable zero-order process, and (b) renally via a first-order process. Lower UFH doses are primarily cleared via enzymatic processes, while higher doses are primarily renally eliminated. Clearance of UFH can be impaired in patients with renal and hepatic dysfunction. Patients with active thrombosis may require higher UFH doses due to a more rapid elimination or variations in the plasma concentrations of heparin-binding proteins. AT deficiency and elevated factor VIII levels are common in pregnant patients. AT deficiency has been linked to higher UFH dose requirements. The requirement of these higher UFH doses is termed "heparin resistance." Factor VIII elevations can result in altered aPTT response to UFH and monitoring with antifactor Xa levels is recommended.4,29

The dose of UFH required to achieve a therapeutic anticoagulant response is correlated to the patient's weight.4 Weight-based dosing regimens should be utilized in order to exceed the therapeutic threshold in the first 24 hours after initiating treat-ment.30 Achieving a therapeutic aPTT in the first 24 hours after initiating UFH is critical because this has been shown to lower the risk of recurrent VTE.4,30 For nonobese patients, the actual body weight should be used to calculate the initial UFH dose (Table 10-5). For obese patients, using the actual body weight to calculate the initial dose is also generally recommended; however, data are more limited in morbidly obese patients; that is, weight greater than 150 kg (330 lb). Some experts recommend using an adjusted body weight (ABW) in these patients instead. The infusion rate is then adjusted based on laboratory monitoring of the patient's response. UFH can also be administered via the SC route; however, IV infusion is preferred by most clinicians because it can be dosed more precisely. If the SC route is selected, an initial 5,000 unit

IV bolus should be given followed by 17,500 units given SC every 12 hours. Subse-

17 23 31

quent doses of SC-UFH need to be adjusted based on the patient's response. ' ' Alternatively, in patients with DVT, a fixed-dose, weight-based dose of unmonitored UFH regimen can also be used with an initial dose of 333 units/kg followed by 250 units/kg given SC every 12 hours.

17,32

17,32

FIGURE 10-6. Mechanism of action of unfractionated heparin, low-molecular weight heparin (LMWH), and fondaparinux. (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:338.)

FIGURE 10-6. Mechanism of action of unfractionated heparin, low-molecular weight heparin (LMWH), and fondaparinux. (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:338.)

© Due to significant variability in interpatient response and changes in patient response over time, UFH requires close monitoring and periodic dose adjustment. The response to UFH can be monitored using a variety of laboratory tests including the aPTT, the whole blood clotting time, activated clotting time (ACT), antifactor Xa

4,33

activity, and the plasma heparin concentration. Although it has several limitations, the aPTT is the most widely used test in clinical practice to monitor UFH. Traditionally, therapeutic aPTT range is defined as 1.5 to 2.5 times the control aPTT value. However, due to variations in the reagents and instruments used to measure the aPTT in different laboratories, each institution should establish a therapeutic range for UFH. The institution-specific therapy range should correlate with a plasma heparin concentration of 0.2 to 0.4 units/mL by protamine titration or 0.3 to 0.7 units/mL by an

4,33

amidolytic antifactor Xa assay. ' An aPTT should be obtained at baseline, 6 hours after initiating the heparin infusion, and 6 hours after each dose change, as this is the time required to reach steady state. The UFH dose is then adjusted based on the aPTT measurement and the institutional-specific therapeutic range (Table 10-5). In patients with "heparin resistance," antifactor Xa concentrations may be a more accurate meth-

4,33

od of monitoring the patient's response. '

Table 10-5 Weight-Baseda Dosing for UFH Administered by Continuous IV Infusion for VTE

Initial Loading Dose

Initial Infusion Rate

SO units/kg {maximum -10,000 units)

aPTT (seconds)

Less than 37 (or less than 12 seconds below Institution-Specific therapeutic rangé)

37-47(oi 1-12 seconds below inst itut ion-speci fit: the ra peu E ic range)

4fi-7t (within institut ion-ipecific therapeutic range)

72-93 {or 1-22 seconds above institution-specific therapeutic range)

Greater than 93 (or greater than 22 seconds above institutiori-spGcffit therapeutic range)

18 untts/kg/b (maximum = 2,300 ufiftVh}

Maintenance Infusion Rate

Dose Adjustment

SO units/kg bolus then increase infusion by 4 units/kg/h

40 units/kg bolus then increase infusion by 2 units/kg/h

No(hange

Decrease infusion by 2 units/kg/h

Hold infusion for ï hour then decrease by 3 units/kg/h aPTX activated partial thromboplastin time; IBW, ideal body weight; UFH, unfractionated heparin.

*Use actual body weight for all calculations. Adjusted body weight (ABW) may be used for morbidly obese patients (greater than 130% Of IRW).

Side effects associated with UFH include bleeding, thrombocytopenia, hypersens-itivity reactions, and with prolonged use, alopecia, hyperkalemia, and osteoporos-

A 9Q

is. ' Bleeding is the most common adverse effect associated with antithrombotic drugs, including UFH therapy. A patient's risk of major hemorrhage is related to the intensity and stability of therapy, age, concurrent drug use, history of GI bleeding, risk of falls or trauma, and recent surgery. Several risk factors can increase the risk of UFH-induced bleeding (Table 10-6). The risk of bleeding is related to the intensity of anticoagulation. Higher aPTT values are associated with an increased risk of bleeding. The risk of major bleeding is 1% to 5% during the first few days of treatment. In addition to the aPTT, hemoglobin, hematocrit, and blood pressure should also be monitored. Concurrent use of UFH with other antithrombotic agents, such as thrombolytics and antiplatelet agents, also increases the risk of bleeding. Patients receiving UFH therapy should be closely monitored for signs and symptoms of bleeding, including epistaxis, hemoptysis, hematuria, hematochezia, melena, severe headache, and joint pain. If major bleeding occurs, UFH should be stopped immediately and the source of bleeding treated.3,4 If necessary, use protamine sulfate to reverse the effects of UFH. The usual dose is 1 mg protamine sulfate per 100 units of UFH, up to a maximum of 50 mg, given as a slow IV infusion over 10 minutes. The effects of UFH are neutralized in 5 minutes, and the effects of protamine persist for 2 hours. If the bleeding is not controlled or the anticoagulant effect rebounds, repeated doses of protamine may be administered.4

Table 10-6 Risk Factors for Major Bleeding While Taking Anticoagulation Therapy

Anticoagulation intensity (e.g., INR greater than 5, aPTT greater than 120 seconds)

Initiation of therapy (first few days and weeks)

Unstable anticoagulation response

Age greater than 65 years

Concurrent antiplatelet drug use

Concurrent nonsteroidal anti-inflammatory drug or aspirin use

History of GI bleeding

Recent surgery or trauma

High risk for fall/trauma

Heavy alcohol use

Renal failure

Cerebrovascular disease

Malignancy aPTT, activated partial thromboplastin time; INR, International Normalized Ratio.

Heparin-induced thrombocytopenia (HIT) is a very serious adverse effect associated with UFH use. Platelet counts should be monitored every 2 to 3 days during the course of UFH therapy.4 HIT should be suspected if the platelet count drops by more than 50% from baseline or to below 120 x 103/mm3 (120 x 109/L). HIT should also be suspected if thrombosis occurs despite UFH use. Immediate discontinuation of all heparin-containing products, including the use of LMWHs is in order. Alternative anticoagulation should be initiated. In patients with contraindications to anticoagulation therapy, UFH should not be administered (Table 10-7).

UFH is an FDA pregnancy category C drug and may be used to treat VTE during pregnancy. UFH should be used with caution in the peripartum period due to the risk of maternal hemorrhage. UFH is not secreted into the breast milk and is safe for use by women who wish to breast-feed.11 For the treatment of VTE in children, the UFH dose is 50 units/kg bolus followed by an infusion of 20,000 units/m per 24 hours. Alternatively, a loading dose of 75 units/kg followed by an infusion of 28 units/kg/h if less than 12 months old and 20 units/kg/h if greater than 1 year old may be con-sidered.34

Low-Molecular Weight Heparins

The LMWHs are smaller heparin fragments obtained by chemical or enzymatic de-polymerization of UFH. LMWHs are heterogeneous mixtures of glycosaminoglycans, and each product has slightly different molecular weight distributions and pharmaco-logic properties.4 Compared with UFH, LMWHs have improved pharmacodynamic and pharmacokinetic properties. They exhibit less binding to plasma and cellular proteins, resulting in a more predictable anticoagulant response. Consequently, routine monitoring of anticoagulation activity and dose adjustments are not required in the majority of patients. LMWHs have longer plasma half-lives, allowing once-or twice-daily administration, improved SC bio availability, and dose-independent renal clearance. In addition, LMWHs have a more favorable side effect profile than UFH. They are also associated with a lower incidence of HIT and osteopenia. Three LMWHs are currently available in the United States: dalteparin, enoxaparin, and tinzaparin.4,29

Like UFH, LMWHs prevent the propagation and growth of formed thrombi. The anticoagulant effect is mediated through a specific pentasaccharide sequence that binds to AT. The primary difference in the pharmacologic activity of UFH and

LMWH is their relative inhibition of thrombin (factor IIa) and factor Xa. Smaller heparin fragments cannot bind AT and thrombin simultaneously (Fig. 10-6). Due to their smaller chain length, LMWHs have relatively greater activity against factor Xa and inhibit thrombin to a lesser degree. The antifactor Xa:IIa activity ratio for the LMWHs ranges from 2:1 to 4:1. The SC bioavailability of the LMWHs is greater than 90%. The peak anticoagulant effect of the LMWHs is reached 3 to 5 hours after a SC dose. The elimination half-life is 3 to 6 hours and is agent-specific. In patients with renal impairment, the half-life of LMWHs is prolonged.4,29

Table 10-7 Contraindications to Anticoagulation Therapy

General

Active bleeding

Hemophilia or other hemorrhagic tendencies Severe liver disease with elevated baseline PT

Severe thrombocytopenia (platelet count less than 20 x 10-7mmJ[20x10;7L]) Malignant hypertension

Inability to meticulously supervise and monitor treatment Product-Specific Contraindications UFH

Hypersensitivity to UFH History of HIT LMWHs

Hypersensitivity to LMWH, UFH, pork products, methylparaben, or propylparaben History of HIT or suspected HIT Fondaparinux

Hypersensitivity to fondaparinux

Severe renal insufficiency (CrCI less than 30 mL/min)

Body weight less than 50 kg (110 lb)

Bacterial endocarditis

Thrombocytopenia with a positive in vitro test for antiplatelet antibodies in the presence of fondaparinux

Lepirudin

Hypersensitivity to hirudins Argatroban

Hypersensitivity to argatroban Warfarin

Hypersensitivity to warfarin Pregnancy

History of warfarin-induced skin necrosis Inability to obtain follow-up PT/INR measurements Inappropriate medication use or lifestyle behaviors

CrCI, creatinine clearance; HIT, heparin-induced thrombocytopenia; INR, International Normalized Ratio; LMWHs, low-molecular weight heparins; PT, prothrombin time; UFH, unfractionated heparin.

The dose of LMWHs for the treatment of VTE is determined based on the patient's weight and is administered SC once or twice daily (Table 10-3). Once-daily dosing of enoxaparin appears to be as effective as twice-daily dosing; however, some data suggest that twice-daily dosing may be more effective in patients who are obese or have 17 23 35

cancer. ' ' The dose of enoxaparin is expressed in milligrams, whereas the doses of dalteparin and tinzaparin are expressed in units of antifactor Xa activity. Due to their predictable anticoagulant effect, routine monitoring is not necessary in the majority of patients.4 LMWHs have been evaluated in a large number of randomized trials and have been shown to be at least as safe and effective as UFH for the treatment 17 23

of VTE. ' Indeed, the rate of mortality was lower in patients treated with a LMWH in clinical trials. This mortality benefit was primarily seen in patients with cancer.31,36

Prior to initiating treatment with a LMWH, baseline laboratory tests should include prothrombin time (PT)/INR, aPTT, CBC, and serum creatinine. Monitor the CBC with platelet count every 2 to 3 days during the first 2 weeks of therapy, and every 2 to 4 weeks with extended use.4 Use LMWHs cautiously in patients with renal impairment due to the potential of drug accumulation and risk of bleeding. Specific dosing recommendations for patients with a creatinine clearance (CrCl) less than 30 mL/min are currently available for enoxaparin but are lacking for other agents of the class (Table 10-3). Higher mortality rate has been reported in elderly patients with renal dysfunction who were treated with the LMWH tinzaparin. Current guidelines recom mend the use of UFH over LMWH in patients with severe renal dysfunction (CrCl less than 30 mL/min).17,37

Most patients with an uncomplicated DVT can be managed safely at home. LMWHs can be easily administered in the outpatient setting, thus enabling the treatment of VTE at home. Several large clinical trials have demonstrated the efficacy and

17 20 31

safety of LMWHs for outpatient treatment of DVT Acceptance of this treat ment approach has increased tremendously over the last several years among clinicians. Patients with DVT with normal vital signs, low-bleeding risk, no other comor-bid conditions requiring hospitalization, and who are stable, may have anticoagulant initiated at home. Although the treatment of patients with PE in the outpatient setting is controversial, patients with submassive PE who are hemodynamically stable can be safely treated in the outpatient setting as well.17,26 Patients considered for outpatient therapy must be reliable or have adequate caregiver support and must be able to strictly adhere to the prescribed treatment regimen and recommended follow-up visits. Close patient follow-up is critical to the success of any outpatient DVT treatment program. Home DVT treatment results in cost savings and improved patient satisfaction and quality of life.20,37,38

Laboratory methods of measuring a patient's response to LMWH maybe warranted in certain situations.4,39 Although controversial, measurement of antifactor Xa activity has been the most widely used method in clinical practice and is recommended by

the College of American Pathologists. Monitoring of antifactor Xa activity may be considered in adult patients who are morbidly obese (weight greater than 150 kg [330 lb] or BMI greater than 50 kg/m ), weigh less than 50 kg (110 lb), or have significant renal impairment (CrCl less than 30 mL/min). Laboratory monitoring may also be useful in children and pregnant women. When monitoring antifactor Xa activity, the sample should be obtained approximately 4 hours after the SC dose is administered, when peak concentration is anticipated. The therapeutic range for antifactor Xa activity has not been clearly defined, and there is a limited correlation between antifactor

Xa activity and safety or efficacy. For the treatment of VTE, an acceptable antifactor Xa activity range is 0.5 to 1 unit/mL with twice-daily dosing. In patients treated with once-daily LMWH regimens, a target level between 1 and 2 units/mL is recommended by some experts.4, 7,35,39

Similar to UFH, bleeding is the major complication associated with LMWHs. The frequency of major bleeding appears to be numerically lower with LMWHs than with UFH.31 The incidence of major bleeding reported in clinical trials is less than 3%.17

Minor bleeding, especially bruising at the injection site, occurs frequently. Protamine sulfate will partially reverse the anticoagulant effects of the LMWHs and should be administered in the event of major bleeding. Due to its limited binding to LMWH chains, protamine only neutralizes 60% of their antithrombotic activity. If the LMWH was administered within the previous 8 hours, give 1 mg protamine sulfate per 1 mg of enoxaparin or 100 antifactor Xa units of dalteparin or tinzaparin. If the bleeding is not controlled, give 0.5 mg of protamine sulfate for every antifactor Xa 100 units of LMWH. Give smaller protamine doses if more than 8 hours have lapsed since the last LMWH dose4

The incidence of HIT is lower with LMWHs than with UFH. However, LMWHs cross-react with heparin antibodies in vitro and should not be given as an alternative anticoagulant in patients with a diagnosis or history of HIT. Monitor platelet counts every few days during the first 2 weeks and periodically thereafter.4

In patients undergoing spinal and epidural anesthesia or spinal puncture, spinal and epidural hematomas have been linked to the use of LMWHs. In patients with in-dwelling epidural catheters, concurrent use of LMWHs and all other agents that impact hemostasis should be avoided. When inserting and removing the in-dwelling epidural catheters, the timing of LMWH administration around catheter manipulation should be carefully coordinated. Catheter manipulation should only occur at minimal or trough anticoagulant levels.4

LMWHs are an excellent alternative to UFH for the treatment of VTE in pregnant women.11 The LMWHs do not cross the placenta, and they are FDA pregnancy category B. Because the pharmacokinetics of LMWHs may change during pregnancy, monitor antifactor Xa activity every 4 to 6 weeks to make dose adjustments.11, LMWHs have also been used to treat VTE in pediatric patients. Children less than 1 year old require higher doses (e.g., enoxaparin 1.5 mg/kg SC every 12 hours). Monitor antifactor Xa activity to guide dosing in children.3

Factor Xa Inhibitors

Fondaparinux, the first agent in this class, is an indirect inhibitor of factor Xa, and exerts its anticoagulant activity by accelerating AT. Fondaparinux contains the specific five-saccharide sequence found in UFH that is responsible for its pharmacolo-gic activity. Due to its small size, fondaparinux exerts inhibitory activity specifically against factor Xa and has no effect on thrombin (factor IIa; Fig. 10-6)29,41 Fondaparinux is currently the only agent of the class that is commercially available in the United States. Idraparinux, rivaroxaban, and apixaban are antifactor Xa inhibitors currently undergoing Phase III clinical trials. Fondaparinux and idraparinux are administered SC; rivaroxaban and apixaban are administered orally. After SC administration, fondaparinux is completely absorbed, and peak plasma concentrations are reached within 2 to 3 hours.41-42

As synthetic drugs (unlike UFH and the LMWHs), factor Xa inhibitors cannot transmit animal pathogens, are consistent from batch-to-batch, and are available in an unlimited supply. Other favorable attributes of factor Xa inhibitors include a predictable and linear dose-response relationship, rapid onset of activity, and long half-life.29,41,42 Factor Xa inhibitors do not require routine coagulation monitoring or dose adjustments. Fondaparinux has a half-life of 17 to 21 hours, permitting once-daily administration, but the anticoagulant effects of fondaparinux will persist for 2 to 4 days after stopping the drug. In patients with renal impairment, the anticoagulant effect persists even longer. Idraparinux has a significantly longer duration of activity and is being developed for once-weekly injection. The oral agents, rivaroxaban and apixaban, have half-lives ranging from 5 to 14 hours allowing once-or twice-daily administration.41,42 Neither fondaparinux nor idraparinux are metabolized in the liver and therefore have few drug interactions. However, concurrent use with other antithrombotic agents increases the risk of bleeding. Unlike the heparins, factor Xa inhibitors do not affect platelet function and do not react with the heparin platelet factor-4 (PF-4) antibodies seen in patients with HIT. Some centers use fondaparinux in patients with subacute HIT or a history of HIT who require anticoagulation ther-4,29,41

apy.

Fondaparinux has been evaluated for the treatment of DVT and PE in two large phase 3 trials and is approved by the FDA for these indications. Fondaparinux is as safe and effective as IV UFH for the treatment of PE and SC LMWH for DVT treatment.43,44 The recommended dose for fondaparinux in the treatment of VTE is based on the patient's weight (Table 10-3). Fondaparinux is renally eliminated and accumulation can occur in patients with renal dysfunction. Due to the lack of specific dosing guidelines, fondaparinux is contraindicated in patients with severe renal impairment (CrCl less than 30 mL/min). Baseline renal function should be measured and monitored closely during the course of therapy. Based on limited available data at this time, monitoring antifactor Xa activity to guide fondaparinux dosing is not recom-mended4,17,29

As with other anticoagulants, the major side effect associated with fondaparinux is bleeding. Fondaparinux should be used with caution in elderly patients because their risk of bleeding is higher. Patients receiving fondaparinux should be carefully monitored for signs and symptoms of bleeding. A CBC should be obtained at baseline and monitored periodically to detect the possibility of occult bleeding. In the event of major bleeding, fresh frozen plasma and factor concentrates should be given. In the case of a life-threatening bleed, recombinant factor VIIa may be considered, but this is a very costly option and it can also increase the risk of thrombosis. Fondaparinux is not

reversed by protamine.

Fondaparinux is pregnancy category B, but there are very limited data regarding its use during pregnancy. Use in pediatric patients has not been studied.4,29,41

DTIs

Given that thrombin is the central mediator of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. DTIs bind thrombin and prevent interactions with its substrates (Fig. 10-7). Several injectable DTIs are approved for use in the United States including lepirudin, bivalirudin, argatroban, and desirudin. Several oral DTIs are currently in development. These agents differ in terms of their chemical structure, molecular weight, and binding to the thrombin molecule. Potential advantages of DTIs include a targeted specificity for thrombin, the ability to inactivate clot-bound thrombin, and an absence of platelet interactions that can lead to HIT. Unlike heparins, DTIs do not require AT as a cofactor and do not bind to plasma proteins. Therefore they produce a more predictable anticoagulant effect. DTIs are considered the drugs of choice for the treatment of VTE in patients with a diagnosis or history of HIT29,41,45

The prototype of this class is hirudin, which was originally isolated from the salivary glands of the medicinal leech, Hirudo medicinalis. Hirudin itself is not commercially available, but recombinant technology has permitted production of hirudin derivatives, namely lepirudin and desirudin.29, 1,45 Lepirudin has a short half-life of approximately 40 minutes after IV administration and 120 minutes when given SC. Elimination of lepirudin is primarily renal; therefore, doses must be adjusted based on the patient's renal function. The dose should be monitored and adjusted to achieve an aPTT ratio of 1.5 to 2.5 times the baseline measurement. Lepirudin is currently approved for use in patients with HIT and related thrombosis. Up to 40% of patients treated with lepirudin will develop antibodies to the drug.29,41,45

FIGURE 10-7. Mechanism of action of direct thrombin inhibitors. (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:345.)

Bivalirudin, a smaller-molecular-weight DTI, is given by IV infusion. Bivalirudin has a shorter elimination half-life (approximately 25 minutes) than lepirudin and is only partially eliminated renally. Unlike lepirudin, bivalirudin is a reversible inhibitor of thrombin and provides transient antithrombotic activity. Patients with moderate or severe renal impairment (CrCl less than 60 mL/min) may require dose adjustment because clearance of bivalirudin is reduced by approximately 20% in these patients. Bivalirudin is approved for use in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. The ACT is used to monitor the anticoagulant effect of bivalirudin during percutaneous coronary intervention (PCI).29'41'45

Desirudin is a SC administered DTI approved for VTE prevention after hip replacement surgery but is not yet commercially available in the United States. Desirudin has an elimination half-life of 2 to 3 hours and is typically dosed every 12 hours. It is primarily eliminated through the kidneys, so dose reduction is needed in patients with renal impairment. The aPTT should be used to measure desirudin's anticoagu-, ..29 41 45

lant activity.29'41'45

Argatroban is a small synthetic molecule that binds reversibly to the active site of-thrombin (Fig. 10-7). Argatroban is IV administered and has a 40-to 50-minute elimination half-life. The aPTT must be monitored to assess its anticoagulant activity. Argatroban is hepatically metabolized; therefore, dose reductions and careful monitoring are recommended in patients with hepatic dysfunction. Renal impairment has no influence on the elimination half-life or dosing of argatroban. Argatroban is approved for prevention and treatment of thrombosis in patients with HIT and in patients with HIT undergoing PCI.29'41'45

Small-molecule DTIs have been structurally modified for oral administration. Several oral DTIs are in development. Dabigatran is one of the oral DTI agents that is in the most advanced phases of clinical development. Dabigatran is undergoing phase 3 clinical trials for the treatment and prevention of VTE and for stroke prevention in patients with atrial fibrillation. The potential advantages of oral DTIs include the ability to give them in fixed once-or twice-daily doses' and without the need for routine coagulation monitoring. In addition' there appear to be a significantly lower number of drug and food interactions associated with oral DTIs as compared to some of the traditional oral anticoagulants such as warfarin.41'45

Contraindications to the use of DTIs and risk factors for bleeding are similar to those of other antithrombotic agents (Tables 10-6 and 10-7). Bleeding is the most common side effect reported with the use of DTIs. Concurrent use of DTIs with thrombolytics significantly increases bleeding complications. Currently' there are no known antidotes to reverse the effects of the DTIs. Fresh frozen plasma' factor concentrates' or recombinant factor VIIa should be given in the event of a major bleed. DTIs can increase the PT/INR and can interfere with the accuracy of monitoring and dosing of warfarin therapy. Data on the use of DTIs in pregnancy and pediatric pa. ,2941 45 tients are very limited.

Warfarin

Warfarin has been the primary oral anticoagulant used in the United States for the past 60 years. Warfarin is the anticoagulant of choice when long-term or extended anticoagulation is required. Warfarin is FDA-approved for the prevention and treatment of VTE, as well as the prevention of thromboembolic complications in patients with myocardial infarction, atrial fibrillation, and heart valve replacement. While very effective, warfarin has a narrow therapeutic index, requiring frequent dose adjustments

5,29

and careful patient monitoring.

Warfarin exerts its anticoagulant effect by inhibiting the production of the vitamin K-dependent coagulation factors II (prothrombin), VII, IX, and X, as well as the anticoagulant proteins C and S (Fig. 10-8). Warfarin has no effect on circulating coagulation factors that have been previously formed, and its full antithrombotic activity is delayed for 5 to 7 days, and potentially longer in slower metabolizers. This delay is related to half-lives of the clotting factors: 60 to 100 hours for factor II (prothrombin), 6 to 8 hours for factor VII, 20 to 30 hours for factor IX, and 24 to 40 hours for factor X. Proteins C and S, the natural anticoagulants, are inhibited more rapidly due to their shorter half-lives, 8 to 10 hours and 40 to 60 hours, respectively. Reductions in the concentration of natural anticoagulants before the clotting factors are depleted can lead to a paradoxical hypercoagulable state during the first few days of warfarin therapy. It is for this reason that patients with acute thrombosis should receive a fast-acting anticoagulant (heparin, LMWH, or fondaparinux) while transitioning to warfarin therapy. ,20,29

Warfarin is a racemic mixture of two isomers, the S and the R forms. The S-isomer is two to five times more potent than the R-isomer. Both isomers are extensively bound to albumin. The two isomers are metabolized in the liver via several isoenzymes including cytochrome P-450 (CYP) 1A2, 2C9, 2C19, 2C18, and 3A4 (Fig. 10-8). Hepatic metabolism of warfarin varies greatly among patients, leading to very large interpatient differences in dose requirements and genetic variations in these isoenzymes; specifically, polymorphisms in the CYP2C9*2, CYP2C9*3 genotype result in significantly lower warfarin dose requirement to achieve a therapeutic response, and VKORC1 haplotype mutations can result in hereditary warfarin resistance and increased warfarin requirements.5 Several algorithms that incorporate CYP2C9 genotype and the VKORC1 haplotype with other patient characteristics to predict warfarin maintenance dosing requirements have been developed and are being tested in large populations. Whether pharmacogenomic-based dosing will improve clinical outcomes has yet to be determined and is not recommended at this time, but it does hold promise for a more personalized approach to warfarin dosing.5'46

FIGURE 10-8. Pharmacologic activity and metabolism of warfarin. (CYP, cytochrome P-450 isoenzyme.) (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:347.)

Warfarin does not follow linear kinetics. Small dose adjustments can lead to large changes in anticoagulant response. The dose of warfarin is determined by each patient's individual response to therapy and the desired intensity of anticoagulation. In addition to hepatic metabolism, warfarin dose requirements are influenced by diet, drug-drug interactions, and health status. Therefore, the dose of warfarin must be de-

5 20 29

termined by frequent clinical and laboratory monitoring. While there are conflicting data regarding the optimal warfarin induction regimen, most patients can start with 5 mg daily, and subsequent doses are determined based on INR response (Fig. 10-9). When initiating therapy, it is difficult to predict the precise warfarin maintenance dose that a patient will require. Patients who are younger (less than 55 years of age) and otherwise healthy can safely use higher warfarin "initiation" doses (e.g., 7.5 or 10 mg). A more conservative "initiation" dose (e.g., 5 mg or less) should be given to elderly patients (greater than 75 years of age), patients with heart failure, liver disease, or poor nutritional status, and patients who are taking interacting medications

5,23

or are at high risk of bleeding. ' Loading doses of warfarin (e.g., 15 to 20 mg) are not recommended. These large doses can lead to the false impression that a therapeutic INR has been achieved in 2 to 3 days and lead to potential future overdosing.5 Before initiating therapy, screen the patient for any contraindications to anticoagulation therapy and risk factors for major bleeding (Tables 10-6 and 10-7). In addition, conduct a thorough medication history including the use of prescription and over-the-counter drugs, and any herbal supplements to detect interactions that may affect warfarin dosing requirements. In patients with acute VTE, a rapid-acting anticoagulant (UFH, LMWH, or fondaparinux) should be overlapped with warfarin for a minimum of 5 days and until the INR is greater than 2 and stable. This is important because the full antithrombotic effect will not be reached until 5 to 7 days or even longer after

5 17

initiating warfarin therapy. ' The typical maintenance dose of warfarin for most patients will be between 25 and 55 mg per week, although some patients require higher or lower doses. Adjustments in the maintenance warfarin dose should be determined based on the total weekly dose and by reducing or increasing the weekly dose by increments of 5% to 25%. When adjusting the maintenance dose, wait at least 7 days to ensure that a steady state has been attained on the new dose before checking the INR again. Checking the INR too soon can lead to inappropriate dose adjustments and unstable anticoagulation status.5

O Warfarin requires frequent laboratory monitoring to ensure optimal outcomes and minimize complications. The PT is the most frequently used test to monitor warfarin's anticoagulant effect. The PT measures the biological activity of factors II, VII, and X. Due to wide variation in reagent sensitivity, different thromboplastins will result in different PT results, potentially leading to inappropriate dosing decisions.5 In order to standardize result reporting, the World Health Organization (WHO) developed a reference thromboplastin and recommended the INR to monitor warfarin therapy. The INR corrects for the differences in thromboplastin reagents and uses the following formula: INR =(PTPatient/PTControl)ISI. The International Sensitivity Index (IST) is a measure of the thromboplastin's responsiveness compared to the WHO reference.5 The goal or target INR for each patient is based on the indication for warfarin therapy. For the treatment and prevention of VTE, the INR target is 2.5 with an acceptable range of 2 to 3. In certain high-risk patients (e.g., certain mechanical heart valves), a higher target INR of 3 with a range of 2.5 to 3.5 is recommended.5 Before initiating warfarin therapy, a baseline PT/INR and CBC should be obtained. After initiating warfarin therapy, the INR should be monitored at least every 2 to 3 days during the first week of therapy. Once a stable response to therapy is achieved, INR monitoring is performed less frequently, weekly for the first 1 to 2 weeks, then

5 47

every 2 weeks, and monthly thereafter. At each encounter, the patient should be carefully questioned regarding any factors that may influence the INR result. These factors include adherence to therapy, the use of interacting medications, consumption of vitamin K-rich foods, alcohol use, and general health status. Patients should also be questioned about symptoms related to bleeding and thromboembolic events. Warfarin dose adjustments should take into account not only the INR result, but also patient-related factors that influence the result. Structured anticoagulation therapy management services (anticoagulation clinics) have been demonstrated to improve the efficacy and

5,47

safety of warfarin therapy when compared to "usual" medical care. ' Some patients engage in self-testing and self-management by using a point of care PT/INR device approved for home use. Highly motivated and well-trained patients are good candid-

5,47

ates for self-testing or self-management.

Can n PT/INR be obtained daily?

Slart warijirin with 5 mg ciaiJy

Consider 7.5-10-mg dose if pelieni age lew iK»ar» 60: no concurrent uw of inlerading m=diCB!ions. and tieec nj risk is low

Measure PT/INR an day 2

:NR iese 1har 1.5—Md dose charge INR= t.5-1.9—DMrease d«a 25-50% INR = 2-2.5—Diirease diiie 50-75% IN ft grealer than 2.5—now next doss

Mpssure PT/lHfi on d* y 3

INiR less than 1jS—Increase dose 0-25% iNR = 15-1.9— No dose change INF = 2-2 5— Decrease dose 25-50% INR gnealer than 2.5—Dec-reaK 50% or hold next dose

Measure PT/INR on day 4

INR = 1,6-1 9—No dose change or increase 10-25% INH = 2-3— Decrease dose 0-25% INR greater than 3—Decrease 50% or hold nexi tisse

Measure' PT.-'ll-jn an day 5 INR iesi than V5—Increase dosu 25% INR = 1.5-1.9—Increase dosa 0-2S% INR = 2-3—No dose Change qw decrease dose 10-25% ■ Nfl greater man 3—Decrease 25-50%

FIGURE 10-9. Initiation of warfarin therapy. (INR, International Normalized Ratio; PT, prothrombin time.) (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:350.)

Similar to other anticoagulants, warfarin'sprimary side effect is bleeding. Warfarin can "unmask" an existing lesion. The incidence of warfarin-related bleeding appears to be highest during the first few weeks of therapy. The annual incidence of major bleeding ranges from 1% to 10% depending on the quality of warfarin therapy management. Bleeding in the GI tract is most common. Intracranial hemorrhage (ICH) is one of the most serious complications, as it often causes severe disability and death. The intensity of anticoagulation therapy is related to bleeding risk. Higher INRs result in higher bleeding risk, and the risk of ICH increases when the INR exceeds 4. ' Instability and wide fluctuations in the INR are also associated with higher bleeding risk. In cases of warfarin overdose or over-anticoagulation, vitamin K may be used to reverse warfarin's effect ( ).5 Vitamin K can be given by the IV

or oral route; the SC route is not recommended. When given SC, vitamin K is erratically absorbed and frequently ineffective. The IV route is reserved for cases of severe warfarin overdose (e.g., INR greater than 20) or major bleeding. Anaphylactoid reactions have been reported with rapid IV administration, therefore slow infusion is recommended. An oral dose of vitamin K will reduce the INR within 24 hours. If the INR is still elevated after 24 hours, another dose of oral vitamin K can be given. The dose of vitamin K should be based on the INR elevation. A dose of 1 to 2.5 mg is sufficient when the INR is between 5 and 9, but 5 mg may be required for INRs greater than 9. Higher doses (e.g., 10 mg) can lead to prolonged warfarin resistance. In cases of life-threatening bleeding, fresh frozen plasma or clotting factor concentrates should be administered, in addition to IV vitamin K. In patients in whom the INR is less than 9 and there is no active bleeding or imminent risk of bleeding, simply withholding warfarin until the INR decreases to within therapeutic range and reducing the weekly dose with more frequent monitoring is appropriate.5

FIGURE 10-10. Management of an elevated INR in patients taking warfarin. Dose reductions should be made by determining the weekly warfarin dose and reducing the weekly dose by 10% to 25% based on the degree of INR elevation. Conditions that increase the risk of thromboembolic complications include history of hypercoagulability disorders (e.g., protein C or S deficiency, presence of antiphospholipid antibodies, antithrombin deficiency, or activated protein C resistance), arterial or venous thrombosis within the previous month, thromboembolism associated with malignancy, mechanical mitral valve in conjunction with atrial fibrillation, previous stroke, poor ventricular function, or coexisting mechanical aortic valve. (INR, International Normalized Ratio.) (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:353.)

FIGURE 10-10. Management of an elevated INR in patients taking warfarin. Dose reductions should be made by determining the weekly warfarin dose and reducing the weekly dose by 10% to 25% based on the degree of INR elevation. Conditions that increase the risk of thromboembolic complications include history of hypercoagulability disorders (e.g., protein C or S deficiency, presence of antiphospholipid antibodies, antithrombin deficiency, or activated protein C resistance), arterial or venous thrombosis within the previous month, thromboembolism associated with malignancy, mechanical mitral valve in conjunction with atrial fibrillation, previous stroke, poor ventricular function, or coexisting mechanical aortic valve. (INR, International Normalized Ratio.) (From Haines ST, Witt DM, Nutescu EA. Venous thromboembolism. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008:353.)

Nonhemorrhagic side effects related to warfarin are rare but can be severe when they occur. Warfarin-induced skin necrosis presents as an eggplant-colored skin lesion or a maculopapular rash that can progress to necrotic gangrene. It usually manifests in fatty areas such as the abdomen, buttocks, and breasts. The incidence is less than 0.1%, and it generally appears during the first week of therapy. Patients with protein C or S deficiency or those who receive large loading doses of warfarin are at greatest risk.5,11 The mechanism is thought to be due to imbalances between procoagulant and anticoagulant proteins early in the course of warfarin therapy. Warfarin-induced purple toe syndrome is another rare side effect; patients present with a purplish discoloration of their toes. If these side effects are suspected, warfarin therapy should be discontinued immediately and an alternative anticoagulant given. There is a theoretical risk that warfarin may cause accelerated bone loss with long-term use, but to date there is no evidence to support this concern. Warfarin is teratogenic and is FDA pregnancy category X. It should be avoided during pregnancy, and women of child-bearing potential should be instructed to use an effective form of contraception. UFH and LMWH are the agents of choice for the treatment of VTE during pregnancy.5,11

® Warfarin is prone to numerous clinically significant drug-drug and drug-food interactions (Tables 10-8, 10-9, and 10-10). Patients on warfarin should be questioned at every encounter to assess for any potential interactions with foods, drugs, herbal products, and nutritional supplements. When an interacting drug is initiated or discontinued, more frequent monitoring should be instituted. In addition, the dose of warfarin can be modified (increased or decreased) in anticipation of the expected

5 48

impact on the INR . ' Warfarin-related drug interactions can generally be divided into two major categories: pharmacokinetic and pharmacodynamic. Pharmacokinet-ic interactions are most commonly due to changes in hepatic metabolism or vitamins that can interact with warfarin.49 Patients on warfarin may experience changes in the INR due to fluctuating intake of dietary vitamin K. Patients should be instructed to maintain a consistent diet and avoid large fluctuations in vitamin K intake rather than strictly avoiding vitamin K-rich foods.

Table 10-8 Clinically Significant Warfarin Drug Interactions

Increase

Decrease

Anticoagulation

Anticoagulation

Increase

Effect (t INR)

Effect (i INR)

Bleeding Risk

Acetaminophen

Arno barbital

Argatroban

Alcohol binge

Butabarbital

Aspirin

Allopurinol

Carbamazepine

Clopidogrel

Amiodarone

Cholestyramine

Danaparoid

Cephalosporins

Dicloxacillin

Dipyridamole

(with MTP side chain)

Griseofulvin

LMWHs

Chloral hydrate

Nafcillin

Nonsteroidal

Chloramphenicol

Phénobarbital

arti-inflamm.

Cimetidine

Phenytoin

drugs

Ciprofloxacin

Primidone

liclopidine

Clofibrate

Rifampin

UFH

Danazol

Secobarbital

Disulfiram

Sucralfate

Doxycycline

Vitamin K

Erythromycin

Fenofibrate

Fluconazole

Fluorouracil

Fluoxetine

Fluvoxamine

Gemfibrozil

Influenza vaccine

Itraconazole

L.ova statin

Metronidazole

Miconazole

Moxa]actam

Neomycin

Norfloxacin

Ofloxacin

Omeprazole

Phenylbutazone

Piroxicam

Propafenone

Prüpoyxphene

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