THE APhA COMPLETE REVIEW FOR PHARMACY, 7th Ed

37. Thromboembolic Disease - Gale Hamann, PharmD, BCPS, CDE

37-1. Venous Thromboembolic Disease

Definition and Epidemiology

Venous thromboembolism (VTE) is a disease process that involves the development of a deep venous thrombosis (DVT), a pulmonary embolism (PE), or both.

pulmonary embolism is a thrombus or foreign substance from the systemic circulation that lodges in the pulmonary artery or its branches and causes a complete or partial occlusion of pulmonary blood flow.

deep venous thrombosis is a thrombus that forms most commonly in the popliteal or femoral veins, the veins of the calf, or the iliac veins of the upper leg. Veins of the upper extremities are less commonly involved.

Approximately 2 million Americans develop VTE each year; 600,000 people in this group have VTE manifested as a PE, and of these, 200,000 die. It is estimated that 1 million Americans will develop a clinically silent PE that goes undiagnosed.

Complications of VTE are postthrombotic syndrome and pulmonary hypertension. Postthrombotic syndrome is characterized as swelling in the affected lower extremity after a DVT. Pulmonary hypertension is a complication that can occur after a PE and is characterized by elevated arterial pressures in the pulmonary vasculature.

The incidence of VTE increases with age and doubles in each decade of life after age 50. VTE costs an estimated $1.5 billion annually.

Clinical Presentation

The most common symptoms of a PE are dyspnea, cough, hemoptysis, tachypnea, tachycardia, pleuritic chest pain, diaphoresis, and overwhelming anxiety. The patient may be cyanotic and hypoxemic secondary to having a reduced ability to oxygenate the blood. Patients with a massive PE may present with syncope. The mortality rate of a PE ranges from 2.3% to 17%.

The most common symptoms of a DVT are pain, tenderness, edema, and erythema of the affected extremity. Other symptoms may include dilation of the superficial veins, a palpable cord, and a positive Homans' sign.

Pathophysiology

Venous thrombi generally form in areas of the veins where blood flow is slowed or disrupted. Often they begin as small thrombi in the large venous sinuses of a valve cusp pocket in the veins of the calf or thigh. Trauma to the vessel causes the release of tissue factor. Tissue factor, in turn, activates the coagulation cascade. This activity results in the formation of thrombin and ultimately the formation of fibrin to form clots. Other common factors that can precipitate the development of a thrombus include disrupted blood flow from immobility or hypercoagulability.

Risk factors for VTE include the following:

• Age over 40 years

• Prolonged immobility

• Major surgery involving the abdomen, pelvis, and lower extremities

• Trauma, especially fractures of the hips, pelvis, and lower extremities

• Malignancy

• Pregnancy

• Previous VTE

• Congestive heart failure or cardiomyopathy

• Stroke

• Acute myocardial infarction

• Indwelling central venous catheter

• Hypercoagulability

• Estrogen therapy

• Varicose veins

• Obesity

• Inflammatory bowel disease

• Nephrotic syndrome

• Myeloproliferative disease

A PE is the result of a dislodged thrombus that is embolized from a thrombus in the deep venous structures of the legs, pelvis, or arms. The embolus travels to the lungs, where it is trapped in the pulmonary arterial microvasculature. Blood flow is obstructed from the PE, which leads to lung edema and reduced pulmonary compliance. This condition results in inadequate oxygen exchange, leading to hypoxemia. Blood flow in the pulmonary artery increases right ventricular afterload, which may lead to right ventricular dilation, dysfunction, and ischemia.

Diagnosis

A DVT is diagnosed on the basis of a detailed history and clinical symptoms. A duplex ultrasound, which measures both blood flow and compressibility of the affected vessel, confirms the diagnosis.

A PE is diagnosed based on a detailed history and clinical symptoms. A spiral CT (computed tomography) scan or a ventilation-perfusion scan confirms the diagnosis.

VTE Prophylaxis

Table 37-1 shows recommendations for VTE prophylaxis.

VTE Treatment

VTE treatment success with unfractionated heparin (UFH) is related to obtaining therapeutic activated partial thromboplastin time (aPTT) levels as rapidly as possible (

Table 37-2). Studies have indicated that the VTE recurrence risk is 20-25% higher if aPTT levels are not within the therapeutic range at 24 hours. The therapeutic range for an aPTT is determined by an antifactor Xa chromogenic assay of 0.3-0.7 IU/mL.

The use of low molecular weight heparin (LMWH) has enabled treatment of a DVT to move from a hospitalization of 5-7 days to either a hospital stay of 1-2 days or outpatient management (

Table 37-3).

[Table 37-1. Recommendations for VTE Prophylaxis]

[Table 37-2. Guidelines for Anticoagulation: IV Unfractionated Heparin]

[Table 37-3. Guidelines for Anticoagulation: LMWH or Fondaparinux]

With outpatient DVT treatment, the diagnosis may take place in either a physician's office or the emergency department. After a Doppler ultrasound confirms the diagnosis of a DVT, the patient is educated on administration of LMWH and receives the first dose of LMWH at that time. After those steps, LMWH and warfarin are administered on an outpatient basis. Warfarin is monitored with an international normalized ratio (INR) at 1- or 2-day intervals. After two therapeutic INRs, the LMWH may be discontinued; warfarin is continued for at least 3 months, and the patient is evaluated for long-term anticoagulation or as indicated (

Table 37-4).

Drug Therapy

Unfractionated heparin

Mechanism of action

UFH binds to antithrombin (AT) and converts it from a slow progressive thrombin inhibitor to a rapid thrombin inhibitor. This, in turn, catalyzes inactivation of factors XIIa, XIa, IXa, Xa, and IIa (thrombin).

[Table 37-4. Duration of Anticoagulation Therapy]

Patient counseling

Patients need to monitor for signs and symptoms of bleeding or bruising, especially at surgical sites.

Therapeutic use

• Prevention and treatment of VTE

• Prevention of VTE in patients with a previous VTE or a known hypercoagulability

• Prophylaxis for VTE in high-risk populations

• Prevention of a mural thrombosis after myocardial infarction (MI)

• Treatment of patients with unstable angina and MI

• Prevention of acute thrombosis after coronary thrombolysis

Parameters to monitor

Heparin is monitored by an aPTT, which is sensitive to the inhibitory effects of heparin on factors IIa (thrombin), Xa, and IXa.

The College of American Pathologists and the American College of Chest Physicians (ACCP) recommend against the use of a fixed aPTT therapeutic range of 1.5-2.5 times a control aPTT. They do recommend that a therapeutic aPTT range be established on the basis of an antifactor Xa concentration of 0.3-0.7 units/mL.

An aPTT should be measured 6 hours after a bolus dose of heparin or after any dosage change and then every 6 hours until a therapeutic aPTT is reached. Once a therapeutic aPTT is achieved, an aPTT may be evaluated every 24 hours.

Platelet count and hematocrit should be evaluated at baseline and every 1-3 days.

Pharmacokinetics

The pharmacokinetics of heparin differs depending on whether an intravenous (IV) or subcutaneous (SC) route of administration is used.

Heparin is cleared from the body by a rapid saturable mechanism that occurs at therapeutic doses. A second, slower unsaturable first-order clearance that is largely by renal means occurs at high doses.

The half-life of heparin varies from approximately 30 minutes after an IV bolus of 25 international units (IU)/kg to 60 minutes after an IV bolus at 100 IU/kg.

Dosing

Heparin should be dosed using a weight-based nomogram. A therapeutic range for heparin is determined by an antifactor Xa chromogenic assay of 0.3-0.7 IU/mL. Weight-based dosing nomograms are effective in achieving a therapeutic aPTT, although they are not universally transferable to every hospital. Published nomograms are specific only for the reagent and instrument used to validate that nomogram.

Determining a therapeutic range by using the calculation of 1.5-2.5 times the mean control aPTT may be erroneous. Previous weight-based nomograms, which use a therapeutic range based on the calculation of 1.5-2.5 times the control aPTT, have been recognized to be accurate only for that aPTT reagent used.

Table 37-5 is an example of a weight-based dosing nomogram. Each hospital should develop its own nomogram based on its therapeutic range.

[Table 37-5. Body Weight-Based Dosing of IV Heparin]

Another approach to heparin therapy is to administer an IV bolus of 5,000 IU followed by a continuous infusion of at least 30,000-35,000 IU over 24 hours. The infusion rate is adjusted to maintain a therapeutic aPTT.

UFH may be administered subcutaneously every 12 hours. The patient should receive an initial dose of 17,500 IU or 250 IU/kg SC q12h. The dose should be adjusted to an aPTT that corresponds to a plasma heparin level of antifactor Xa chromogenic assay of 0.3-0.7 IU/mL. This level should be measured 6 hours after the injection.

Alternatively, UFH may be administered as a fixed dose that is unmonitored. An initial dose of 333 IU/kg is administered, followed by 250 IU/kg SC every 12 hours.

Adverse effects

The most common adverse effects are minor bleeding in the form of gingival bleeding, epistaxis, and ecchymosis. The most common serious adverse effects of heparin are gastrointestinal or urogenital bleeding.

Fatal or life-threatening adverse effects often result from intracranial or retroperitoneal bleeding.

Transient thrombocytopenia may occur within the first 2-4 days of therapy, which will resolve with continued therapy. Heparin-induced thrombocytopenia may also occur, which requires discontinuation of the heparin.

Osteoporosis is a risk with chronic use.

Contraindications

Contraindications include the following:

• Active bleeding

• Severe uncontrolled hypertension

• History of heparin-induced thrombocytopenia

Use epidural or spinal anesthesia with caution because patients are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis.

LMWHs and pentasaccharides

Table 37-6 describes LMWH and pentasaccharide dosage forms. The pharmacokinetics of LMWHs and pentasaccharides are described in

Table 37-7.

Mechanism of action

LMWHs inhibit factor Xa and, to a much lesser extent, factor IIa.

[Table 37-6. LMWH and Pentasaccharide Dosage Forms]

Fondaparinux is a pentasaccharide. It binds selectively to AT, which potentiates the inactivation of factor Xa in the coagulation cascades, thus inhibiting the formation of thrombin.

Advantages of LMWH and fondaparinux over UFH

• LMWHs and fondaparinux have fewer interactions with plasma proteins; thus, they have a more predictable response at lower doses.

• LMWHs have a much longer half-life, which allows them to be administered subcutaneously every 12-24 hours.

• Fondaparinux has a half-life of 17-21 hours, which allows dosing every 24 hours.

• LMWHs have a lower incidence of osteoporosis and heparin-induced thrombocytopenia. Fondaparinux does not cause heparin-induced thrombocytopenia and can be used as an anticoagulant to treat heparin-induced thrombocytopenia.

Therapeutic use

• Prevention and treatment of VTE

• Prevention of VTE in patients with a previous VTE or a known hypercoagulability

• Prophylaxis for VTE in high-risk populations

• Arterial embolism prevention in patients with mechanical or tissue prosthetic heart valve replacement

• Arterial embolism prevention in patients with atrial fibrillation or atrial flutter

• Arterial embolism prevention in patients with an acute cardioembolic stroke

[Table 37-7. Pharmacokinetics of LMWHs and Pentasaccharides]

Parameters to monitor

Monitor platelet counts, hematocrit and hemoglobin, and signs and symptoms of bleeding.

Bone mineral density should be monitored with long-term use.

Anti-Xa heparin levels can be monitored in obese patients or in patients receiving LMWH who have significant renal impairment. Anti-Xa levels should be drawn 4 hours after a dose. Therapeutic levels are 0.6-1.0 IU/mL for twice-daily dosing and 1-2 IU/mL for once-daily dosing. The therapeutic range for daltaparin is 0.5-1.5 IU/mL 4-6 hours after receiving 3-4 doses.

Prothrombin time (PT)/INR and aPTT are not useful in monitoring LMWH.

Currently, fondaparinux has no direct monitoring parameters.

Dosing LMWH and fondaparinux

See

Tables 37-8 and

37-9 for dosage requirements.

Patient counseling

• Strict compliance is necessary to ensure a consistent level of anticoagulation.

• Notify a health care provider if an increase occurs in bruising, hematuria, melena, hemoptysis, epistaxis, or gingival bleeding or if any other abnormal bleeding happens.

• Consult a health care provider or pharmacist before taking any over-the-counter medications.

• Avoid aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs).

• The air bubble in the LMWH or fondaparinux syringe should be near the plunger prior to injection. This method ensures that all of the drug is expelled from the syringe and helps minimize the amount of bleeding, bruising, and hematoma formation from the injection site.

Adverse effects

The most common adverse effects are minor bleeding in the form of gingival bleeding, epistaxis, and ecchymosis. The most common serious adverse effects of heparin are gastrointestinal or urogenital bleeding.

[Table 37-8. Indications and Recommended Doses of LMWH and Fondaparinux]

Fatal or life-threatening adverse effects often result from intracranial or retroperitoneal bleeding.

Heparin-induced thrombocytopenia can occur with LMWH, but its incidence is greater with UFH.

Osteoporosis can occur with chronic use.

Direct thrombin inhibitors

Direct thrombin inhibitors are as follows:

• Lepirudin (Refludan)

• Argatroban

Mechanism of action

Lepirudin is a recombinant DNA-derived polypeptide nearly identical to hirudin. It produces an anticoagulant effect by binding directly to thrombin and does not require AT to yield its effect. Lepirudin does not bind to other plasma proteins as heparin does.

Argatroban is a synthetic molecule that reversibly binds to thrombin.

Therapeutic use

Lepirudin is used for the treatment of DVT and heparin-induced thrombocytopenia.

Argatroban is used for treatment of heparin-induced thrombocytopenia and percutaneous coronary intervention.

Pharmacokinetics

Lepirudin has a half-life of 1-2 hours. Approximately 45% of lepirudin is eliminated by the kidneys.

Argatroban is metabolized in the liver to inactive metabolites. The half-life is 0.5-1 hour.

Parameters to monitor

Lepirudin

Monitor complete blood count (CBC) and signs and symptoms of bleeding.

Monitor the therapeutic effect by measuring the aPTT 4 hours after beginning therapy and after a dosage change. After the aPTT is stable within the therapeutic range, daily monitoring is sufficient.

[Table 37-9. Enoxaparin Dosage Regimens for Patients with Severe Renal Impairment (Creatinine Clearance < 30 mL/min)]

Argatroban

Monitor CBC and signs and symptoms of bleeding. The aPTT is used to monitor and adjust argatroban therapy. The aPTT should be drawn 2 hours after an infusion is started and after each dosage change.

Argatroban will also elevate a PT/INR. For patients on concomitant warfarin therapy, this effect may impede monitoring and make proper assessment of the INR difficult. For combination therapy, argatroban may be discontinued after an INR is greater than 4. An INR should be drawn after 4-6 hours. If the INR is in the therapeutic range, continue with warfarin only. If the INR is below the therapeutic range, restart argatroban and increase the dose of warfarin. Repeat this procedure until the INR is within the therapeutic range.

Dosing

Lepirudin

Administer a bolus dose of 0.4 mg/kg IV over 15-20 seconds with an infusion of 0.15 mg/kg/h. Measure an aPTT 4 hours after the infusion. Titrate the infusion to a therapeutic range. The therapeutic range is a target range aPTT ratio of 1.5 to 2.5. If the aPTT is below the therapeutic range, increase the infusion by 20%. If the aPTT is above the therapeutic range, hold the infusion for 2 hours, and then decrease the infusion by 50%. Four hours after a dosage change, aPTTs should be measured.

Argatroban

Administer a continuous IV infusion at the rate of 2 mcg/kg/min. Adjust infusion rate to maintain an aPTT ratio of 1.5 to 2.5. The usual dose is 2-10 mcg/kg/min.

The dose should be reduced in moderate hepatic insufficiency. A continuous IV infusion should begin at a rate of 0.5 mcg/kg/min. Because of the prolonged elimination half-life, measure an aPTT 4 hours after initiation or a dosage change.

Patient counseling

Monitor symptoms of bruising and bleeding, and report them to a health care provider immediately.

Adverse effects

The most common adverse effects are minor bleeding in the form of gingival bleeding, epistaxis, and ecchymosis. The most common serious adverse effects are gastrointestinal or urogenital bleeding.

Fatal or life-threatening adverse effects often result from intracranial or retroperitoneal bleeding.

There is no known antidote for lepirudin or argatroban. The anticoagulant effect declines rapidly after discontinuation of the drug.

Nonhemorrhagic effects such as fever, nausea, vomiting, and allergic reactions rarely occur.

Warfarin (Coumadin)

Dosage forms

• Tablets: 1 mg (pink), 2 mg (lavender), 2.5 mg (green), 3 mg (tan), 4 mg (blue), 5 mg (peach), 6 mg (teal), 7.5 mg (yellow), and 10 mg (white)

• Injections (IV): 5 mg powder for reconstitution (2 mg/mL)

Mechanism of action

Warfarin is a vitamin K antagonist that produces its pharmacologic effect by interfering with the intercon-version of vitamin K and its 2,3-epoxide (vitamin K epoxide). Warfarin leads to the depletion or reduction in activity of vitamin K-dependent coagulation proteins (factors II, VII, IX, and X) produced in the liver. The level and activity of the vitamin K-dependent clotting factors decline over 6-96 hours. At least 4-5 days of warfarin therapy are necessary before a patient is completely anticoagulated.

Therapeutic use

• Prevention and treatment of VTE

• Prevention of VTE in patients with a previous VTE or a known hypercoagulability

• Prophylaxis for VTE in high-risk populations

• Prevention of arterial embolism in patients with mechanical or tissue prosthetic heart valve replacement

• Prevention of arterial embolism in patients with atrial fibrillation or atrial flutter

• Prevention of arterial embolism in patients with a previous cardioembolic stroke

• Prevention of acute MI in patients with peripheral arterial disease

Patient counseling

• Warfarin should be taken at the same time every day.

• Strict compliance is necessary to ensure a consistent level of anticoagulation.

• Strict compliance with a consistent vitamin K diet is necessary to ensure a consistent level of anticoagulation.

• Notify the health care provider in the event of hematuria, melena, epistaxis, hemoptysis, increased bruising, or any abnormal bleeding.

• Notify all health care providers, including dentists, of warfarin therapy.

• Blood monitoring to determine an adequate level of anticoagulation and compliance is necessary at regular intervals.

• Consult the health care provider or pharmacist before taking any new prescription or over-the-counter medications.

• Avoid aspirin or NSAIDs unless instructed otherwise by a physician.

• Women of childbearing age should use an effective form of birth control because warfarin has teratogenic effects.

Parameters to monitor

Warfarin therapy is monitored by a prothrombin time. The PT responds to a reduction in factors II, VII, and X. The INR is used to standardize the responsiveness of thromboplastin to the anticoagulant effects of warfarin. The INR is calculated by the following equation:

INR = (observed PT/mean normal PT)ISI

ISI is the International Sensitivity Index, which is a measure of thromboplastin sensitivity. The lower the ISI is, the more responsive the thromboplastin is to the anticoagulant effects of warfarin.

The ACCP Evidenced-Based Clinical Practice Guidelines (8th edition) recommends two intensities of anticoagulation: a less intense level with a target INR of 2.5 and a range of 2.0-3.0, and a high-intensity level of anticoagulation with a target INR of 3.0 and a range of 2.5-3.5 (

Table 37-10).

Upon initiation of warfarin therapy, the INR should be evaluated daily if the patient is in the hospital and every 2-3 days if the patient is not hospitalized.

Pharmacokinetics

Warfarin is a racemic mixture of two optically active isomers, warfarin S and warfarin R, in roughly equal amounts. The S isomer is five times more potent than the R isomer.

Warfarin is rapidly and completely absorbed from the gastrointestinal tract with peak concentration in approximately 90 minutes. Warfarin is 99% protein-bound with a half-life of 36-42 hours.

The onset of anticoagulation occurs after 4-5 days of therapy and is caused by the depletion of the clotting factors rather than steady-state concentrations of warfarin. Thus, the onset of action is based on the half-life of the clotting factors II, VII, IX, and X.

Dosing

Time in the therapeutic range and intensity of anticoagulation are critical for optimizing the therapeutic efficacy of warfarin and minimizing the risk of hemorrhage.

Warfarin initiation does not require loading. Loading doses can result in an inappropriate increase in the INR, which is not reflective of an anticoagulant effect.

Initiating warfarin at 5 mg daily should result in an INR around 2.0 in 4-5 days for most patients. An alternative method is to administer between 5 and 10 mg for the first 1 or 2 days and then adjust the dose depending on the INR response.

Initiating warfarin at a dose of ≤ 5 mg daily may be appropriate in the elderly; in patients with liver disease, heart failure, or malnutrition; in patients taking drugs known to increase the responsiveness to warfarin; or in patients with a high risk of bleeding.

Initiating warfarin at a dose of 7.5-10 mg daily may be appropriate for young, healthy, or obese patients.

If a rapid anticoagulant effect is indicated, IV heparin, LMWH, or fondaparinux should be administered along with warfarin for at least 4-5 days until a therapeutic INR is reached. Heparin, LMWH, or

[Table 37-10. Recommended Therapeutic Ranges for Oral Anticoagulation]

fondaparinux may be discontinued when the INR is within the therapeutic range on two consecutive occasions.

Disease state interaction

Disease states that can increase the response to warfarin are hyperthyroidism, congestive heart failure, liver disease, fever, and genetic warfarin increased sensitivity.

Disease states that can decrease the response to warfarin are hypothyroidism and genetic warfarin resistance. Patient nonadherence can also result in a reduced warfarin response.

Drug-drug interactions

Warfarin is a drug with a narrow therapeutic index. Numerous drugs interact with warfarin to potentiate or reduce its anticoagulant effect. Because the S isomer is five times more active than the R isomer, drugs that inhibit or induce the S isomer will have a more significant effect on warfarin than drugs that inhibit or induce the R isomer (

Table 37-11).

Drug-food interactions

Foods that contain high amounts of vitamin K can reduce the anticoagulant effect of warfarin (Table 37-11). It is important that patients be consistent in their consumption of these foods and that they evenly space their consumption over a 7-day period. If a patient suddenly stops eating these foods, the INR may dramatically increase.

Adverse effects

The most common adverse effect is minor bleeding in the form of gingival bleeding, epistaxis, and ecchymosis. The most common serious adverse effects of warfarin are either gastrointestinal or urogenital bleeding.

Warfarin-induced skin necrosis is a rare, but serious adverse effect. Skin necrosis begins within 10 days of warfarin initiation. It is characterized by painful, erythematous lesions on breast, thighs, and buttocks, which may progress to hemorrhagic lesions. It may be associated with protein C deficiency and, to a lesser effect, protein S deficiency. The concomitant use of

[Table 37-11. Drugs and Foods That Can Interact with Warfarin]

UFH, LMWH, or fondaparinux with initiation of warfarin can prevent its occurrence.

Purple toe syndrome is a dark blue-tinged discoloration of the feet that occurs rarely 3-8 weeks after warfarin initiation.

Fatal or life-threatening adverse effects are related to intracranial or retroperitoneal bleeding. Box 37-1 outlines the treatment guidelines for the management of elevated INRs or bleeding.

Special precautions must be taken for patients undergoing invasive procedures.

Table 37-12 outlines the risk stratifications for perioperative arterial or venous thromboembolism. Box 37-2 outlines the recommendations for managing anticoagulation in these patients.

37-2. Atrial Fibrillation

Definition and Epidemiology

Atrial fibrillation (AF) is a supraventricular tachyarrhythmia characterized by uncoordinated atrial activity up to 300-500 beats per minute that is associated with an irregular ventricular response. Uncontrolled AF can result in a rapid ventricular response, which can affect blood circulation. AF may be chronic or paroxysmal in nature.

Box 37-1. Management of Elevated INRs or Bleeding in Patients Receiving Vitamin K Antagonists

INR Above Therapeutic Range But < 5.0; No Significant Bleeding

Lower dose or omit dose, monitor more frequently, and resume at lower dose when INR is therapeutic. If INR is only minimally above therapeutic range, no dose reduction may be required.

INR ≥ 5.0 But < 9.0; No Significant Bleeding

Omit the next one or two doses, monitor more frequently, and resume at an appropriately adjusted dose when the INR is in the therapeutic range.

Alternatively, omit the dose and give vitamin K (1.0-2.5 mg orally), particularly if the patient is at increased risk of bleeding. If more rapid reversal is necessary because the patient requires urgent surgery, vitamin K (≤ 5 mg orally) can be given with the expectation that a reduction of the INR will occur in 24 hours. If the INR is still high, additional vitamin K (1-2 mg orally) can be given.

INR ≥ 9.0; No Significant Bleeding

Hold warfarin therapy and give higher dose of vitamin K (2.5-5.0 mg orally) with the expectation that the INR will be reduced substantially in 24-48 hours. Monitor more frequently and use additional vitamin K if necessary. Resume therapy at an appropriately adjusted dose when the INR is therapeutic.

Serious Bleeding at Any Elevation of INR

Hold warfarin therapy and give vitamin K (10 mg by slow IV infusion), supplemented with fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa, depending on the urgency of the situation. Vitamin K can be repeated every 12 hours.

Life-threatening Bleeding

Hold warfarin therapy and give fresh-frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa supplement with vitamin K (10 mg by slow IV infusion). Repeat, if necessary, depending on INR.

Reprinted with permission from Ansell J, Hirsh J, Dalen JE, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(suppl 6):160S-98S.

Over 2.2 million Americans have AF, which increases in prevalence after age 45 and greatly accelerates after age 65. An estimated 10% of Americans over the age of 80 have AF.

AF is a risk factor for the development of a stroke. It is estimated that 4.5% of patients with nonvalvular

[Table 37-12. Suggested Patient Risk Stratification for Perioperative Arterial or Venous Thromboembolism]

AF, if untreated, would experience a stroke. If transient ischemic attack and silent stroke are included, the incidence is around 7%.

Box 37-2. Recommendations for Managing Anticoagulation Therapy in Patients Requiring Invasive Procedures

Patients with Low Risk of Thromboembolism

• Discontinue warfarin 5 days prior to procedure.

• Consider bridging with low-dose SC LMWH.

• Suggest therapeutic-dose SC LMWH over other management options.


Patients with Moderate Risk of Thromboembolism

• Discontinue warfarin 5 days prior to procedure.

• Consider bridging with therapeutic-dose SC LMWH or IV UFH or with low-dose SC LMWH over not bridging during interruption of warfarin therapy.

• Suggest therapeutic-dose SC LMWH over other management options.


Patients with High Risk of Thromboembolism

• Discontinue warfarin 5 days prior to procedure.

• Bridge with therapeutic-dose SC LMWH or IV UFH during interruption of warfarin therapy.

• In patients whose INR is still elevated (> 1.5) 1 to 2 days before surgery, administer 1 to 2 mg oral vitamin K to normalize INR.

• Discontinue therapeutic-dose LMWH 24 hours prior to procedure and administer half the total daily dose as the last preoperative dose.

• Discontinue UFH approximately 4 hours before a procedure.

• Suggest LMWH over IV UFH.

• Restart warfarin 12-24 hours after procedure or when hemostasis is adequate.

• Resume therapeutic-dose LMWH approximately 24 hours after the procedure or when hemostasis is adequate.

• In patients at high bleeding risk, delay therapeutic-dose LMWH or UFH for 48-72 hours or administer low-dose LMWH or UFH when hemostasis is secured, or completely avoid LMWH or UFH.

• Individualize treatment plans based on postoperative hemostasis and bleeding risk.


Patients Undergoing Minor Dental or Dermatologic Procedure or Cataract Removal

• Continue warfarin therapy around the time of the procedure.

• Coadminister an oral prohemostatic agent such as tranexamic acid or epsilon amino caproic acid mouthwash for dental procedures.


Adapted with permission from Douketis JD, Berger PB, Dunn AS, et al. The perioperative management of antithrombotic therapy: Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(suppl 6):299S-339S.

The Framingham Heart Study demonstrated that patients with rheumatic heart disease and AF had a 17-fold increase in the incidence of stroke compared to age-matched controls.

Clinical Presentation

AF is characterized by an "irregularly irregular" heartbeat, with the possibility of a rapid ventricular response. Common symptoms are palpitations and fatigue. Patients may complain of their heart "fluttering" and feeling weak.

Drug Therapy

Warfarin therapy has demonstrated approximately a 68% (50-70%) relative risk reduction in stroke in patients with AF, whereas aspirin therapy has demonstrated only a 21% (0-38%) relative risk reduction. A meta-analysis of five studies reported a 36% relative risk reduction in all strokes and a 46% reduction in ischemic strokes with warfarin compared to aspirin. Randomized controlled studies have demonstrated that anticoagulation with warfarin, INR 2-3, is highly effective in reducing the risk of stroke. Warfarin therapy with an INR 1.2-1.5 has not been shown to be effective in stroke prevention; in addition, an INR > 4 was associated with a higher rate of intracranial hemorrhage. Conversely, the risk of bleeding and intracranial hemorrhage is higher with warfarin therapy than with aspirin.

Risk stratification for stroke in AF has been developed (

Tables 37-13 and

37-14).

Table 37-15 gives treatment guidelines for stroke prevention based on risk stratifications.

[Table 37-13. Risk Stratification in AF Based on CHADS2 Score]

[Table 37-14. Stroke Rate Based on CHADS2 Score]

Other Therapy

Cardioversion, described in Box 37-3, is an elective procedure for AF patients.

37-3. Stroke

Definition and Epidemiology

Stroke is defined as a sudden onset of focal neurologic deficit lasting longer than 24 hours.

[Table 37-15. Recommendations for Antithrombotic Therapy in AF]

Box 37-3. Anticoagulation for Elective Cardioversion in Patients with AF

Patients with AF of ≥ 48 hours, or unknown duration, who are scheduled for elective cardioversion should be anticoagulated with warfarin to a target INR of 2.5 with a range of 2.0-3.0 for 3 weeks prior to direct current or pharmacologic cardioversion and for 4 weeks after successful cardioversion. If AF returns, then continue chronic anticoagulation with warfarin at a target INR of 2.5 (range of 2.0-3.0).

Alternatively, such patients should be anticoagulated with IV UFH with a target aPTT of 60 seconds (range of 50-70 seconds), full dose LMWH, or at least 5 days of warfarin with a target INR of 2.5 (range of 2.0-3.0) at the time of cardioversion. Then undergo transesophageal echocardiography (TEE). If no thrombus is seen on TEE and cardioversion is successful, anticoagulation should be continued with a target INR of 2.5 (range of 2.0-3.0) for at least 4 weeks. If a thrombus is seen on TEE, then cardioversion should be postponed and anticoagulation should be continued indefinitely. The TEE should be repeated before attempting cardioversion later.

For patients with AF for < 48 hours in duration, cardioversion may be performed without anticoagulation. However, in patients without a contraindication to anticoagulation, begin IV UFH (target aPTT of 60 seconds; range of 50-70 seconds) or use full-dose LMWH at presentation. If the patient has risk factors for stroke, then a TEE-guided approach is a reasonable alternative strategy.

For emergency cardioversion in hemodynamically unstable patients, IV UFH (target aPTT of 50 seconds; range of 50-70 seconds) should be started as soon as possible, followed by 4 weeks of anticoagulation with warfarin (target INR of 2.5; range of 2.0-3.0).

Oral anticoagulation at the time of cardioversion in patients with atrial flutter is recommended in a manner similar to that used for AF.

Adapted with permission from Singer DE, Alberts GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008(suppl 6);133:546S-92S.

Transient ischemic attack (TIA) is defined as a focal ischemic neurologic deficit usually lasting 2-5 minutes, which resolves completely in less than 24 hours.

After heart disease and cancer, stroke is the third-leading cause of death in America. Approximately 700,000 Americans suffer a stroke each year; 500,000 of these individuals experience their first stroke, and 200,000 experience a recurrent stroke. The incidence of stroke increases with age, and the rate doubles for each decade after age 55.

Hypertension is a factor in 70% of patients who suffer a stroke.

Risk factors for stroke are as follows:

• Hypertension

• Smoking

• Heart disease (coronary heart disease, heart failure, left ventricular hypertrophy, and atrial fibrillation)

• Elevated pulse pressure

• Previous TIA or stroke

• Diabetes

• Hyperlipidemia

• Obesity

Cigarette smoking increases the risk of stroke two to three times compared with the risk in nonsmokers. Atrial fibrillation increases the risk of a stroke six times.

Clinical Presentation

Symptoms of a stroke depend on where the stroke occurred in the brain and the rapidity with which the symptoms develop. One or more TIAs commonly precede a stroke. Symptoms range from focal deficits to more significant deficits, such as hemiplegia or hemiparesthesia, blindness in one eye, or speech difficulties.

Pathophysiology

Fifteen percent of strokes are hemorrhagic in nature. The remaining 85% of strokes are ischemic in nature. In the case of ischemic strokes,

• 20% are cardioembolic.

• 20% are due to atherosclerotic cerebrovascular disease.

• 25% are due to penetrating artery disease or lacunar infarctions.

• 30% are cryptogenic.

• 5% are due to other causes.

Atherosclerosis and plaque formation result in arterial narrowing, which leads to stenosis with reduced blood flow. This condition may enhance platelet aggregation, which can lead to an arterial occlusion. An occlusive clot is present in up to 80% of ischemic strokes.

The Framingham Heart Study indicates that a strong relationship exists between hypertension and the risk of both hemorrhagic and nonhemorrhagic stroke. Atherothrombotic infarctions occur four times more often in patients with hypertension (blood pressure > 165/95 mm Hg) than in patients without hypertension. The treatment of hypertension reduces the incidence of stroke by 35-40%.

Cardioembolic etiology accounts for one-fifth of all ischemic strokes. The most common cause of a cardiac embolism is AF; other factors include valvular heart disease, coronary heart disease, prosthetic heart valves, and dilated cardiomyopathy. A cardioembolic stroke often has an abrupt onset and more commonly involves the middle cerebral artery.

Diagnosis and Prevention

Diagnosis is based on physical examination, medical history, and diagnostic imaging such as CT scan, magnetic resonance imaging (MRI) scan, magnetic resonance angiography (MRA), or cerebral arteriography.

Preventive measures are as follows:

• Maintain blood pressure < 140/90 mm Hg or < 130/90 mm Hg for patients with diabetes or coronary artery disease.

• Control hyperlipidemia with statin therapy (low-density lipoprotein < 100 mg/dL).

• Maintain glycemic control (hemoglobin A1c < 7%).

• Stop smoking.

• Reduce weight if overweight.

• Exercise (i.e., 30 minutes of moderate exercise daily).

• Implement the DASH (Dietary Approaches to Stop Hypertension) diet (low in sodium and saturated fat; high in fruits, vegetables, whole grains, and fiber).

Drug Therapy

Tissue plasminogen activator

Mechanism of action

Because most strokes are caused by a thromboembolic occlusion in an intracranial artery, thrombolytic therapy is key to restoring or improving perfusion. Tissue plasma activator (t-PA) is a plasminogen activator (serine protease) that enhances the conversion of plasminogen to plasmin in the presence of fibrin. t-PA binds to fibrin in a thrombus and converts bound plasminogen to plasmin. Plasmin, an enzyme responsible for clot dissolution, initiates local fibrinolysis.

Indications

Criteria for use in acute treatment of stroke are as follows:

• Onset of symptoms < 3-4.5 hours

• No indication of intracranial hemorrhage from baseline CT scan of the head

• Blood pressure < 185/110 mm Hg

• Platelets > 100,000/mm3

• No conditions present that would increase the patient's likelihood of bleeding

• No heparin therapy within 48 hours with an elevated aPTT

• No oral anticoagulants or an INR > 1.7

• No suspicion of subarachnoid hemorrhage on pretreatment evaluation

• No gastrointestinal or urinary tract hemorrhage within 21 days

• No stroke or serious head injury within 3 months

• No recent (within 3 months) intracranial or intraspinal surgery

• No seizure at the onset of stroke

• No active internal bleeding

• No intracranial neoplasm, arteriovenous malformation, or aneurysm

• No major surgery or serious trauma within 2 weeks

• No clinical symptoms suggesting post-MI or pericarditis

• Not currently pregnant or lactating

Specific treatment guidelines are available to evaluate patient characteristics for the use of t-PA in acute stroke.

Dose

t-PA is administered at a dose of 0.9 mg/kg (maximum dose 90 mg) IV, with 10% of the dose given as an initial bolus over 1 minute and the balance infused over 60 minutes.

Parameters to monitor

Monitor hematocrit, mental status, and signs and symptoms of bleeding.

Adverse drug reactions

Bleeding is the most common adverse effect with t-PA. The most common sites of bleeding are gastrointestinal, urogenital, retroperitoneal, and intracranial.

Contraindications

Contraindications include intracranial hemorrhage, recent stroke, blood pressure > 185/100 mm Hg, active internal hemorrhage, platelets < 100,000/mm3, anticoagulant therapy within 24 hours of t-PA, intracranial neoplasm, arteriovenous malformation, and aneurysm.

Antiplatelet drugs

Aspirin

Mechanism of action

Aspirin produces its antiplatelet effect by irreversibly inactivating the enzyme cyclooxygenase, which prevents the conversion of arachidonic acid to thromboxane A2. Thromboxane A2 stimulates platelet aggregation. The effects of aspirin on platelets occur for the life of the platelet (i.e., approximately 5-7 days). Aspirin has demonstrated a 27-30% risk reduction of stroke.

Patient counseling

• Notify physician if melena, persistent stomach pain or discomfort, breathing difficulties, increased bleeding or bruising, or skin rashes develop.

• Avoid NSAIDs or warfarin unless instructed otherwise by a physician.

• Avoid over-the-counter medications that contain aspirin.

• Do not crush or chew enteric-coated aspirin.

Dose

Within 24-48 hours of an acute ischemic stroke, patients should receive aspirin 325 mg daily. Aspirin is effective for stroke prevention at a dose of 50-325 mg daily.

Monitoring parameters

Signs and symptoms of bleeding should be monitored.

Adverse drug reactions

Adverse drug reactions include nausea, vomiting, dyspepsia, gastrointestinal ulceration, gastric erosion, duodenal ulcers, gastrointestinal hemorrhage, rash, urticaria, angioedema, bronchospasm, and asthma exacerbation.

Drug-drug interactions

Warfarin, UFH, LMWH, NSAIDs, fondaparinux, and clopidogrel may increase the risk of bleeding if used in combination with aspirin.

Drug-disease interactions

Use enteric-coated aspirin after an acute episode of peptic or gastric ulcer disease.

Avoid aspirin use if there is a risk of aspirin-induced asthma.

Clopidogrel (Plavix)

Mechanism of action

Clopidogrel is a selective and irreversible inhibitor of adenosine diphosphate-induced platelet aggregation that does not affect arachidonic acid metabolism. The effects of clopidogrel on platelets occur for the life of the platelet, approximately 5-7 days.

The CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Event) trial demonstrated an 8.7% relative risk reduction of composite outcomes of ischemic stroke, MI, or vascular death with the use of clopidogrel versus aspirin in patients with a recent stroke or MI or in patients with symptomatic peripheral arterial disease. Clopidogrel was most beneficial for patients with peripheral artery disease and showed a 23.8% relative risk reduction over aspirin.

Dose

Clopidogrel is effective in stroke prevention at a dose of 75 mg daily.

Patient counseling

• Notify physician of melena, persistent stomach pain or discomfort, increased bleeding or bruising, or development of a skin rash.

• Avoid NSAIDs or warfarin unless instructed otherwise by a physician.

• Avoid over-the-counter medications that contain aspirin.

Parameters to monitor

Signs and symptoms of bleeding should be monitored.

Adverse drug reactions

Nausea, dyspepsia, diarrhea, abdominal pain, increased bruising, and bleeding may occur.

Drug-drug interaction

Warfarin, aspirin, NSAIDs, UFH, fondaparinux, and LMWH can increase the risk of bleeding if combined with clopidogrel.

Clopidogrel may inhibit cytochrome isoenzyme CYP450-2C9 substrates, thus creating the potential to inhibit the metabolism of fluvastatin, tolbutamide, and torsemide. Close monitoring may be advisable.

Proton pump inhibitors may inhibit the activation of clopidogrel, thus reducing its effectiveness.

Drug-disease interactions

Use clopidogrel with caution in peptic or gastric ulcer disease.

It may require dosage reduction in moderate to severe hepatic dysfunction.

Extended-release dipyridamole plus immediate-release aspirin (Aggrenox)

Mechanism of action

Dipyridamole is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate in the platelet, which potentiates the deaggregating effects of prostacyclin on platelets.

The Second European Stroke Prevention Study demonstrated that a combination of dipyridamole 200 mg and aspirin 25 mg bid showed a 37% stroke risk reduction compared to placebo and reduced the risk of nonfatal and fatal stroke by 23% compared to aspirin.

Patient counseling

• Notify physician of melena, persistent stomach pain or discomfort, breathing difficulties, increased bleeding or bruising, or development of a skin rash.

• Avoid NSAIDs or warfarin unless instructed otherwise by a physician.

• Avoid over-the-counter medications that contain aspirin.

• Take this medication on an empty stomach, 1 hour before or 2 hours after meals. If stomach upset occurs, take it with food or milk.

• Do not crush or chew.

Dose

A combination of extended-release dipyridamole 200 mg with immediate-release aspirin 25 mg in a capsule is taken twice daily.

Parameters to monitor

Signs and symptoms of bleeding should be monitored.

Adverse drug reactions

Adverse reactions include headache, nausea, vomiting, dyspepsia, gastrointestinal ulceration, gastric erosion, duodenal ulcers, gastrointestinal hemorrhage, rash, urticaria, angioedema, hypotension, dizziness, flushing, epistaxis, bronchospasm, and asthma exacerbation.

Drug-drug interactions

Warfarin, UFH, LMWH, NSAIDs, fondaparinux, aspirin, and clopidogrel may increase the risk of bleeding if used in combination with this product.

Drug-disease interaction

Use dipyridamole-aspirin with caution in the presence of peptic or gastric ulcer disease.

37-4. Key Points

• Appropriate VTE prophylaxis should be used with all patients who have risk factors for its development. ACCP Evidenced-Based Clinical Practice Guidelines (8th edition) has guidelines for VTE prophylaxis specific for at-risk patient populations.

• UFH should be administered as a bolus of 80 IU/kg IV, then a maintenance infusion of 18 IU/kg per hour. Heparin is monitored by aPTT levels. A therapeutic aPTT range should be determined for each hospital or laboratory that corresponds to an antifactor Xa concentration of 0.3-0.7 IU/mL.

• LMWH offers a more predictable response at lower doses without the need to monitor levels, except in patients with severe renal impairment or in obesity. It has a lower incidence of osteoporosis and heparin-induced thrombocytopenia. It can also be administered once or twice daily by SC injection, which allows care to shift from the hospital to the outpatient arena.

• An acute VTE should be treated with IV UFH, LMWH, or fondaparinux to provide immediate anticoagulation, followed by the initiation of warfarin therapy. Warfarin should be initiated at 5.0-7.5 mg daily for most patients. Patients with malnutrition, liver disease, or heart failure; patients who are taking drugs known to increase the responsiveness to warfarin; patients who have a high risk for bleeding; or elderly patients may be started at a lower dose. UFH, LMWH, or fondaparinux should be overlapped with warfarin for at least 4-5 days or until two consecutive INRs are within the therapeutic range.

• Patients with a single VTE with reversible, time-limited risk factors should be anticoagulated for 3 months. Patients with a single idiopathic VTE should be anticoagulated for at least 3 months, but consider long-term therapy depending on the risk-benefit ratio. Patients with a recurrent VTE should be anticoagulated long term.

• Atrial fibrillation is a condition that predisposes a patient to the development of a stroke. Warfarin titrated to a target INR of 2.5 with a range of 2.0-3.0 reduces the risk for stroke by approximately 68% (50-70%). Aspirin is not as effective as warfarin in high-risk patients with AF, with an approximately 21% (0-38%) relative risk reduction.

• Patients with a thromboembolic occlusion in an intracranial artery should receive t-PA, provided that the following conditions are met:

• Onset of symptoms is less than 3-4.5 hours.

• CT scan of the head does not indicate an intracranial hemorrhage.

• Blood pressure < 185/100 mm Hg.

• Conditions are not present that would increase the patient's likelihood of bleeding.

• t-PA is administered at a dose of 0.9 mg/kg (maximum dose 90 mg) IV with 10% of the dose given as an initial bolus over 1 minute and the balance infused over 60 minutes.

• The drugs of choice for a noncardioembolic stroke are

• Aspirin 50-325 mg daily

• Clopidogrel 75 mg daily

• Aspirin 25 mg/dipyridamole 200 mg bid

37-5. Questions

1.

A 24-year-old female presents to the emergency department with complaints of severe shortness of breath, dyspnea, and chest pain. She is also experiencing tachycardia and tachypnea. Two days prior she noticed pain and swelling in her left lower extremity. Her past medical history is negative for thrombosis. Her current medications include Tri-Levlen daily and ibuprofen 600 mg q6h prn for pain. A duplex ultrasound of the left lower extremity revealed a DVT. Her vital signs are T, 98.4°; P, 124/min; R, 36/min; BP, 162/100 mm Hg; Wt, 100 kg; Ht, 165 cm. The most likely cause of her shortness of breath, dyspnea, and chest pain is

A. bronchitis.

B. asthma exacerbation.

C. pulmonary embolism.

D. heart failure exacerbation.

E. atrial fibrillation.

 

2.

This patient is started on heparin therapy. Which dosage regimen is most appropriate?

A. IV heparin 20,000 IU bolus, then 5,000 IU/h

B. IV heparin 8,000 IU bolus, then 1,800 IU/h

C. IV heparin 5,000 IU bolus, then 500 IU/h

D. IV heparin 5,000 IU q12h

E. SC heparin 5,000 IU q12h

 

3.

All of the following are risk factors for a DVT except

A. hip replacement surgery.

B. knee replacement surgery.

C. hernia repair surgery.

D. hip fracture surgery.

E. abdominal surgery.

 

4.

Which diagnostic test would be most helpful with the diagnosis of a pulmonary embolism?

A. Chest x-ray

B. Electrocardiogram

C. Spiral CT of the chest

D. Bronchoscopy

E. Echocardiogram

 

5.

A patient is started on warfarin for atrial fibrillation. What is an appropriate starting dose of warfarin?

A. 1 mg daily

B. 5 mg daily

C. 15 mg daily

D. 20 mg daily

E. 25 mg daily

 

6.

What laboratory test is used to monitor heparin therapy?

A. aPTT

B. PT

C. INR

D. Clotting time

E. Factor XIa

 

7.

A 47-year-old patient is diagnosed with a lower-extremity DVT. The patient's height is 6 feet and weight is 220 lb (100 kg). The physician would like to treat this patient on an outpatient basis with warfarin and low molecular weight heparin. Which dose below would be the most appropriate?

A. Enoxaparin 30 mg SC q12h

B. Enoxaparin 40 mg SC q24h

C. Enoxaparin 100 mg SC q12h

D. Enoxaparin 200 mg SC q12h

E. Enoxaparin 220 mg SC q12h

 

8.

How long should enoxaparin be continued in a patient with an acute DVT?

A. At least 4-5 days until the INR is > 2.0 for 24 hours

B. At least 42 days until the INR is > 3.0 for 24 hours

C. At least 24 hours until the INR is > 4.0 for 24 hours

D. At least 48 hours until the INR is > 4.0 for 24 hours

E. At least 7-10 days until the INR is > 3.5 for 24 hours

 

9.

All of the following statements are important information to communicate to a patient on warfarin therapy except

A. Take warfarin every day without missing any doses.

B. Eat a consistent amount of vitamin K-rich foods per week.

C. Report any symptoms of bleeding to your physician.

D. Take warfarin with meals and remain standing for 30 minutes.

E. Do not take aspirin-containing products unless directed to do so by your physician.

 

10.

Vitamin K-rich foods can affect the anticoagulant effect of warfarin. Which of the following foods can decrease the anticoagulant effects of warfarin?

I. Lima beans

II. Spinach

III. Broccoli

A. Only I is correct.

B. Only III is correct.

C. I and II are both correct.

D. II and III are both correct.

E. I, II, and III are correct.

 

11.

Drugs can affect the anticoagulant effect of warfarin. Which of the following drugs can increase the effects of warfarin?

I. Ciprofloxacin

II. Trimethoprim-sulfamethoxazole

III. Fluconazole

A. Only I is correct.

B. Only III is correct.

C. I and II are both correct.

D. II and III are both correct.

E. I, II, and III are correct.

 

12.

What is the most appropriate therapy for a patient with atrial fibrillation, cerebrovascular accident, hypertension, and diabetes?

A. Aspirin 325 mg daily

B. Warfarin 5 mg daily

C. Clopidogrel 75 mg daily

D. t-PA 90 mg daily

E. Aspirin 25 mg/dipyridamole 200 bid

 

13.

A patient presented to the emergency department with symptoms of aphasia and dysarthria, which resolved over the course of 3 days. The patient has a history of hyperlipidemia, type 2 diabetes mellitus, and hypertension.

An echocardiogram showed an ejection fraction of 55%, normal valve function, and normal chamber size. An electrocardiogram showed normal sinus rhythm. Carotid ultrasound indicated moderate stenosis. A CT of the head showed no hemorrhages. Blood pressure was 178/102 mm Hg. Hemoglobin A1c was 10.2%. A lipid profile was as follows: total cholesterol: 294 mg/dL; HDL: 32 mg/dL; LDL: 218 mg/dL; triglycerides: 200 mg/dL. Medications include glipizide 10 mg daily and hydrochlorothiazide 25 mg daily. Which therapy is indicated in this patient?

A. Aspirin 325 mg po daily

B. Clopidogrel 75 mg po bid

C. Aspirin 25 mg/dipyridamole 200 mg po daily

D. Warfarin 5 mg po daily

E. t-PA 90 mg po daily

 

14.

All of the following are other treatment goals for this patient except

A. hemoglobin A1c < 7%.

B. blood pressure < 130/80 mm Hg.

C. LDL < 100 mg/dL.

D. aPTT 70-100 seconds.

E. smoking cessation.

 

15.

Fondaparinux is an anticoagulant that inhibits which clotting factor?

A. IIa

B. IXa

C. Xa

D. XIa

E. VIIa

 

16.

A 58-year-old male is scheduled for a total knee replacement tomorrow. He has a medical history of hypertension, for which he is treated with amlodipine 5 mg daily. His height is 6 feet 2 inches and his weight is 176 lb (80 kg). What form of DVT prophylaxis is indicated in this patient?

I. Enoxaparin 30 mg SC q12h

II. Fondaparinux 2.5 mg SC q24h

III. Aspirin 325 mg daily

A. Only I is correct.

B. Only III is correct.

C. Either I or II are correct.

D. Either II or III are correct.

E. I, II, and III are correct.

 

17.

A 68-year-old male presents to the emergency department with complaints of epistaxis as well as bruising on his arms and legs. He has been taking warfarin 8 mg daily. His INR is 10.2. What is the most appropriate therapy to reverse his warfarin toxicity?

A. Hold warfarin for 4 days; restart warfarin at a lower dose when his INR is < 3.0.

B. Hold warfarin and administer vitamin K 0.5 mg IV; restart warfarin at a lower dose when his INR is < 3.0.

C. Hold warfarin and administer tranexamic acid 10 mg IV; restart warfarin at a lower dose when his INR is < 3.0.

D. Hold warfarin and administer vitamin K 5 mg po; restart warfarin at a lower dose when his INR is < 3.0.

E. Hold warfarin and administer prothrombin complex 5 mg po; restart warfarin at a lower dose when his INR is < 3.0.

 

18.

A 63-year-old is receiving warfarin 7.5 mg daily for atrial fibrillation. What therapeutic INR range is indicated for this patient?

A. 1.0-2.0

B. 1.5-2.5

C. 2.0-3.0

D. 2.0-3.5

E. 2.5-3.5

 

19.

A 56-year-old female presents to the emergency department with complaints of flank pain, dysuria, and increased urinary frequency. She is diagnosed with a urinary tract infection. Her past medical history includes type 2 diabetes mellitus, hypertension, and atrial fibrillation. Her medications include metformin 1 g bid, quinapril 40 mg daily, and warfarin 5 mg daily. What would be the most appropriate antibiotic to treat this patient's UTI?

A. Septra DS bid

B. Ciprofloxacin 500 mg bid

C. Rifampin 300 mg qid

D. Doxycycline 100 mg bid

E. Erythromycin 500 mg qid

 

20.

Which of the following drugs produce action by inhibiting platelet activity?

I. Clopidogrel

II. Dipyridamole

III. t-PA

A. Only I is correct.

B. Only III is correct.

C. I and II are both correct.

D. II and III are both correct.

E. I, II, and III are correct.

 

21.

What color is warfarin 7.5 mg?

A. White

B. Blue

C. Yellow

D. Pink

E. Green

 

22.

Which of the following is a common side effect associated with unfractionated heparin?

A. Hypokalemia

B. Hypoglycemia

C. Ecchymosis

D. Nausea

E. Hyponatremia

 

23.

What is the length of anticoagulation therapy for atrial fibrillation?

A. 3 months

B. 6 months

C. 9 months

D. 12 months

E. Long term

 

24.

Advantages of LMWH over UFH include all of the following except

A. SC administration.

B. no dosage adjustment needed with renal insufficiency.

C. once- or twice-daily dosing.

D. predictable response at lower doses.

E. lower incidence of heparin-induced thrombocytopenia.

 

37-6. Answers

1.

C. Symptoms of shortness of breath, dyspnea, chest pain, tachycardia, and tachypnea, along with a recent history of a DVT, are indications of a pulmonary embolism. A ventilation-perfusion scan or a spiral CT of the chest would confirm the diagnosis.

 

2.

B. Several studies have indicated that weight-based dosing of heparin is more effective in obtaining therapeutic aPTT than standard heparin titration. A weight-based protocol with an 80 IU/kg IV bolus followed by an infusion of 18 IU/kg per hour should produce aPTTs close to the therapeutic range. The other doses are not appropriate.

 

3.

C. High-risk surgeries involve the abdomen and lower extremities; thus, hip and knee replacement as well as hip fracture surgery are major risk factors for the development of a VTE. Hernia repair surgery is considered minor surgery and, unless the patient has other risk factors, would not require DVT prophylaxis other than early ambulation.

 

4.

C. A spiral CT of the chest or a ventilation-perfusion scan would be necessary to confirm the diagnosis of a PE. Chest x-ray, electrocardiogram, echocardiogram, or bronchoscopy would not assist with the diagnosis.

 

5.

B. Warfarin 5 mg daily should result in an INR around 2.0 within 4-5 days. The other doses are either extremely low or high for the majority of patients. Higher doses of warfarin may elevate an INR, but this increase may not be associated with a level of anticoagulation. A rapid increase in INR is due to depletion of factor VII rather than the anticoagulant effect that is associated with depletion of factors II and X.

 

6.

A. An aPTT is the laboratory test used to monitor heparin therapy. An aPTT should be checked 6 hours after a dosage change and every 24 hours if it is within the therapeutic range. A PT/INR is used to monitor warfarin therapy.

 

7.

C. Enoxaparin 100 mg SC q12h or 1 mg/kg SC q12h is the dose for treatment of an acute DVT. Enoxaparin 30 mg SC q12h and 40 mg SC q24h are doses used for DVT prophylaxis. Enoxaparin 200 mg SC q12h and 220 mg SC q12h are extremely high doses.

 

8.

A. For the treatment of an active DVT or PE, at least 4-5 days of heparin or LMWH overlap with warfarin is needed before an anticoagulant effect is produced by warfarin. Heparin or LMWH should be discontinued after an INR is > 2.0 for 24 hours.

 

9.

D. Statements A, B, C, and E are important to discuss with patients on warfarin. Patients should follow strict compliance with warfarin. They should eat vitamin K-rich foods consistently over the course of a week and report any symptoms of bleeding to their physician.

 

10.

D. Green, leafy vegetables contain higher amounts of vitamin K; thus, spinach and broccoli can reduce an INR. Lima beans, although green, do not have a large amount of vitamin K.

 

11.

E. All of these drugs have the potential to produce a major rise in INR. These drugs should not be combined with warfarin if possible.

 

12.

B. In a patient with AF with multiple risk factors for a stroke (hypertension, prior cerebrovascular accident, and diabetes), warfarin is the drug of choice if the patient is a good warfarin candidate. Aspirin and clopidogrel are antiplatelet agents and are not as effective as warfarin in stroke risk reduction. t-PA is used for acute stroke treatment and administered intravenously.

 

13.

A. Aspirin 325 mg daily is correct. Clopidogrel is dosed at 75 mg daily rather than bid. Aspirin 25 mg/dipyridamole 200 mg is dosed bid rather than daily. Warfarin is not appropriate in this patient because there is no indication that this was a cardioembolic stroke (the echocardiogram and electrocardiogram were normal). t-PA is not used orally and is used only for acute treatment of stroke to restore perfusion. Moderate stenosis of the carotid artery indicates atherosclerotic disease is present, and antiplatelet therapy is indicated.

 

14.

D. All of the goals are correct except aPTT range. Because antiplatelet therapy is indicated in this patient, aPTT monitoring is not indicated.

 

15.

C. Fondaparinux inhibits factor Xa.

 

16.

C. Enoxaparin 30 mg SC q12h or fondaparinux 2.5 mg SC q24h are correct. Aspirin is not effective for DVT prophylaxis in knee replacement surgery.

 

17.

D. Warfarin toxicity with an INR of 10.2 can be effectively reversed by holding the dose of warfarin and administering vitamin K 5 mg orally. Warfarin should be restarted when the INR is < 3.0. The IV route is used only in emergent situations because anaphylactic reactions are possible. Prothrombin complex is administered IV only for severe bleeding situations.

 

18.

C. The therapeutic range for oral anticoagulation is an INR of 2.0-3.0, with a target of 2.5. Increased bleeding is associated with an INR > 4.0, and embolic events are more common with an INR < 1.5.

 

19.

D. Doxycycline 100 mg bid would be the most appropriate therapy for a UTI. Septra DS, erythromycin, and ciprofloxacin will interact with warfarin to elevate the INR.

 

20.

C. Clopidogrel and dipyridamole both inhibit antiplatelet activity, and t-PA is a thrombolytic agent.

 

21.

C. Warfarin 7.5 mg is yellow, 1 mg is pink, 10 mg is white, and 4 mg is blue.

 

22.

C. Minor bleeding and bruising are common side effects of heparin therapy. Other common areas for bleeding are the urogenital and gastrointestinal tracts.

 

23.

E. The duration of anticoagulation therapy for patients with AF is lifelong. The risk for stroke is present as long as AF is present. Patients who undergo direct current cardioversion to normal sinus rhythm require anticoagulation therapy for 4 weeks after conversion because the risk of stroke remains high during this period.

 

24.

B. Because LMWHs are renally eliminated, they must be dose-adjusted for creatinine clearance < 30 mL/min. Guidelines have recently been released for enoxaparin dosing in renal impairment. For DVT prophylaxis, enoxaparin should be administered 30 mg SC q24h rather than q12h. For DVT treatment, enoxaparin should be administered 1 mg/kg SC q24h rather than q12h.

 

37-7. References

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