Venous Thromboembolism Chapter 21

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Venous Thromboembolism Chapter 21
Pharmacotherapy A Pathophysiologic Approach
The McGraw-Hill Companies
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Abbreviations
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Overview

• Definition of venous thromboembolism (VTE)
• Pulmonary Embolism (PE)
• Deep Vein Thrombosis (DVT)
• Pharmacologic agents used in VTE management
• Unfractionated Heparin (UFH)
• Low Molecular Weight Heparins (LMWH)
• Fondaparinux
• Direct Thrombin Inhibitors (DTI)
• Warfarin

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Overview

• Venous thromboembolism prevention
• Venous thromboembolism treatment
• Special populations
• Heparin-Induced Thrombocytopenia (HIT)

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Key Concepts

• VTE risk related to several factors (which are
  additive)
• Confirm VTE diagnosis with objective testing
• Antithrombotic therapies require meticulous,
  systematic monitoring ongoing patient education
• Bleeding most common adverse effect associated
  with anticoagulant drugs

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Key Concepts

• All hospitalized patients should receive VTE
  prophylaxis that responds to risk level, continue
  throughout period of risk
• VTE treatment rapid-acting anticoagulant
  overlapped with warfarin for gt 5 days or until
  INR is gt 2.0
• Most patients with uncomplicated DVT PE can be
  safely treated as outpatients

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Venous Thromboembolism

• Clot formation in venous circulation
• gt 50 of patient population with VTE have
  clinically silent disease
• 2 million people in the United States develop
  VTE each year

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Factors Regulating Hemostasis and Thrombosis
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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Clinical Presentation of DVT

• Laboratory tests
• serum D-dimer concentration elevated
• elevated erythrocyte sedimentation rate
• white blood cell count elevation
• Diagnostic tests
• duplex ultrasonography (most common)
• venography or phlebography (gold standard)

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Clinical Presentation of DVT

• Symptoms
• generally nonspecific
• leg pain, swelling, warmth
• Signs
• dilated superficial veins, palpable cord
• Homans sign

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Clinical Presentation of PE

• Commonly develops in patients with identifiable
  risk factors during or following hospitalization
• Some patients develop symptomatic DVT
• Patients may die suddenly before treatment can be
  initiated

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Clinical Presentation of PE

• Symptoms
• cough, chest pain/tightness, shortness of breath,
  palpitation, hemoptysis
• dizziness, lightheadedness with large PE
• symptoms often confused with MI
• Signs
• tachypnea, tachycardia, diaphoresis, distended
  neck veins
• cyanosis or hypotension if large PE
• cardiovascular collapse (cyanosis, shock,
  oliguria)

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Clinical Presentation of PE

• Laboratory tests
• elevated serum D-dimer
• increased erythrocyte sedimentation rate
• white blood cells elevation
• Diagnostic tests
• ventilation-perfusion (V/Q) computerized
  tomography (CT) scans are most common
• pulmonary angiography (gold standard)

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Ventilation-Perfusion Lung Scan
(B) multiple segmental perfusion defects,
indicating a ventilation perfusion mismatch and
high probabiltly of pulmonary embolism.

• normal ventilation

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Diagnosis

• Important to treat VTE quickly aggressively
• Assessment of patient's status should focus on
  search for risk factors
• Venous thrombosis uncommon in absence of risk
  factors, risks are additive
• VTE should be strongly suspected in patients with
  multiple risk factors
• even with mild, seemingly inconsequential
  symptoms

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Unfractionated Heparin (UFH)

• Derived from bovine lung or porcine intestinal
  mucosa
• no differences identified in antithrombotic
  activity
• Heterogeneous mixture of sulfated
  glycosaminoglycans
• Molecular weight of UFH molecules 3,000 to
  30,000 daltons
• mean weight 15,000 daltons
• Anticoagulant profile clearance of UFH
  molecules varies based on length

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Heparin
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UFH Pharmacology

• Anticoagulant effect mediated through specific
  pentasaccharide sequence on heparin molecule that
  binds antithrombin provoking a conformational
  change
• UFHantithrombin complex is 100 to 1,000 times
  more potent than antithrombin alone
• through its action on thrombin, the
  UFHantithrombin complex inhibits
  thrombin-induced activation of factors V VIII

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UFH Pharmacology

• Prevents growth propagation of a formed
  thrombus and allows patient's own thrombolytic
  system to degrade the clot
• Factors IIa (thrombin) Xa most sensitive to
  inhibition by UFHantithrombin complex
• UFHantithrombin complex not capable of
  inactivating thrombin or factor Xa in a formed
  clot or bound to surfaces

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UFH Pharmacology

• At high doses, UFH binds heparin cofactor II,
  further inhibiting thrombin activity
• Increases release of tissue factor pathway
  inhibitor from vascular endothelium
• augment inhibitory effect on factor Xa
• UFH binds platelets inhibits platelet
  aggregation
• especially high-molecular-weight heparin
  fractions

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UFH Pharmacokinetics

• Unreliable PO absorption due to large molecular
  size anionic structure
• Dose dependent subcutaneous bioavailability
• 30 to 70
• Onset of anticoagulant effect 1 to 2 hours after
  SQ injection
• peaks at 3 hours
• Continuous infusion preferred for IV
  administration
• intermittent IV boluses produce relatively high
  peaks in anticoagulation activity greater risk
  of major bleeding

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UFH Pharmacokinetics

• Dose-dependent t½ 30 to 90 minutes
• may be up to 150 min in some patients at high
  doses
• 2 primary elimination mechanisms
• rapid saturable zero-order process heparinases
  desulfatases enzymatically inactivate heparin
  molecules
• slower 1st-order nonsaturable renal elimination
• Low UFH doses cleared principally by saturable,
  rapid, zero-order mechanism
• Renal elimination predominates at very high doses

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UFH Pharmacokinetics

• Renal hepatic dysfunction reduce rate of UFH
  clearance
• Patients with active thrombosis may eliminate UFH
  more rapidly
• possibly due to increased binding to acute phase
  reactants

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UFH Dose Administration

• Dose based on indication, therapeutic goals,
  patients response to therapy
• expressed in units of activity
• For VTE prophylaxis, UFH given by SQ injection in
  abdominal fat layer over the iliac crest
• typical prophylaxis dose 5,000 units every 8 to
  12 hours
• When immediate full anticoagulation required,
  weight-based IV bolus dose followed by continuous
  infusion preferred

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Weight-Baseda UFH Dosing for Continuous IV
Infusion
aUse actual body weight for all calculations.
Adjusted body weight may be used for obese
patients. baPTT may vary based on individual
assays.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
28
UFH Therapeutic Monitoring

• Close monitoring required unpredictable patient
  response
• Activated partial thromboplastin time (aPTT) is
  still used at some institutions
• therapeutic range is institution specific
• sometimes difficult to interpret
• Antifactor Xa level has replaced aPPT at some
  facilities
• provides heparin concentration using a
  calibration curve
• target concentration 0.3 to 0.7 U/ml

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UFH Therapeutic Monitoring

• aPTT limitations
• reagent sensitivity, temperature, phlebotomy
  methods, hemodilution
• diurnal variation, peak response occurring 3 AM
  during continuous IV infusion
• adjusting infusion rates in response to diurnal
  variation could lead to over- or underdosing
• prolonged beyond measurable limits when heparin
  concentration exceeds 1 unit/ml
• lower-weight heparin fragments accumulate but
  have little effect on aPTT in vivo

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UFH Therapeutic Monitoring

• Measure prior to initiation to determine baseline
• IV infusion evaluate response 6 hr after
  initiation or dose change
• Some acute VTE MI patients have diminished
  response to UFH (heparin resistance)
• suspected in patients who require gt 40,000 units
  of UFH per 24-hour period
• adjust dose based on antifactor Xa concentrations

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UFH Adverse Effects

• Primary adverse effect bleeding
• more closely related to underlying risk factors
  than high aPTT
• Presence of concomitant bleeding risks increase
  risk of UFH-induced hemorrhage
• thrombocytopenia
• use of other antithrombotic therapy
• preexisting source of bleeding
• Risk of bleeding increases with age, recent
  surgery, hemostatic defects, heavy alcohol
  consumption, renal failure, peptic ulcer disease,
  neoplasm

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UFH Adverse Effects

• Thrombocytopenia common (platelet count lt
  150,000)
• up to 30 of patients have appreciable decline in
  platelet count
• Heparin-Associated Thrombocytopenia (HAT)
• benign, transient, mild
• generally within the 1st few days of treatment in
  heparin-naive patients
• Heparin-Induced Thrombocytopenia (HIT)
• serious
• requires immediate intervention

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UFH Adverse Effects

• Long-term UFH
• alopecia
• priapism
• suppressed aldosterone synthesis with subsequent
  hyperkalemia
• UFH doses 20,000 units/day for gt 6 months
  associated with significant bone loss may lead
  to osteoporosis
• especially during pregnancy

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UFH Management

• Hemorrhage can occur at any site
• monitoring closely for bleeding signs symptoms
• regular monitoring hemoglobin, hematocrit, BP
• When major bleeding occurs
• discontinue UFH immediately
• identify and treat underlying source of bleeding
• administer IV protamine sulfate 1 mg per 100
  units of UFH (maximum 50 mg) slow IV infusion
  over 10 min
• neutralizes UFH in 5 min
• activity persists for 2 hr

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UFH Special Populations

• Heparin-related compounds (UFH, LMWH)
  anticoagulants of choice during pregnancy
• does not cross the placenta
• Use cautiously during 3rd trimester peripartum
  period
• Not excreted in breast milk
• considered safe while breast-feeding

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UFH Special Populations

• Acute thrombosis treatment in children
• loading dose
• 75 to 100 units/kg over 10 min
• maintenance dose
• 28 units/kg/hr infants up to 12 months of age
• 20 units/kg/hr children gt 1 yr

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Low Molecular Weight Heparin

• Fragments of UFH produced by chemical or
  enzymatic depolymerization
• 1/3 the molecular weight of UFH
• Mean molecular weight is product specific
• 3 LMWHs
• enoxaparin
• dalteparin
• tinzaparin

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Low Molecular Weight Heparin

• Advantages over UFH
• predictable anticoagulation dose response
• improved subcutaneous bioavailability
• dose-independent clearance
• longer biologic t½
• lower incidence of thrombocytopenia
• reduced need for laboratory monitoring

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LMWH Pharmacology

• Prevent growth, propagation of formed thrombi
• Enhance/accelerate antithrombin activity bind
  specific pentasaccharide sequence
• Cause endothelium to release tissue factor
  pathway inhibitor
• enhances inhibition of factor Xa factor VIIa
  inactivation
• Limited activity against thrombin
• proportionally greater antifactor Xa activity

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LMWH Pharmacokinetics

• More predictable anticoagulation response due to
  reduced binding to proteins cells
• Bioavailability 100 when administered
  subcutaneously
• peak anticoagulation effect 3 to 5 hr
• Predominantely renal elimination
• Plasma t½ 2 to 4 times longer than UFH
• Clearance independent of dose

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LMWH Dosing Administration

• Fixed or weight-based dosing based on product
  indication
• Doses based on actual body weight
• capping of dose not recommended for obese
  patients
• Enoxaparin dose
• milligrams
• Dalteparin tinzaparin doses
• units of antifactor Xa activity

42
LMWH Doses
aFDA approved dose for indication.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
43
LMWH Doses
aFDA approved dose for indication.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
44
LMWH Dosing Administration

• Usually given by SQ injection in abdomen or upper
  outer thigh while the patient is supine
• Dosed every 12 to 24 hours depending on
  indication product
• Larger doses given once daily
• significantly higher peak plasma concentrations

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LMWH Dosing Administration

• Elimination t½ with severe renal impairment
• CrCl lt 30 mL/min
• reduce enoxaparin dose
• extend dosing interval to once daily
• pharmacokinetics of dalteparin tinzaparin less
  characterized in renal insufficiency
• studies suggest lower degree of accumulation

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LMWH Therapeutic Monitoring

• Monitoring not necessary due to predictable
  anticoagulant response with SQ administration
• Obtain baseline labs
• PT/INR
• aPTT
• complete blood cell count with platelets
• serum creatinine
• Monitor CBC every 5 to 10 days during the first 2
  weeks
• every 2 to 4 weeks thereafter

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Low Molecular Weight Heparin

• No proven reversal method
• May give IV protamine sulfate
• not recommended if LMWH administered gt 12 hr
  earlier
• Safe in pregnancy, does not cross placenta
• Preferred agents in pediatrics monitor
  antifactor Xa
• Adverse effects
• most common bleeding
• epidural spinal hematomas possible in patients
  with epidural catheters
• thrombocytopenia, avoid with HIT
  history/diagnosis

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Fondaparinux Pharmacology

• Pentasaccharide specifically but reversibly binds
  antithrombin
• Selectively inhibits factor Xa activity
• prevents thrombus generation clot formation
• No direct effect on thrombin activity at
  therapeutic plasma concentrations
• No effect on platelet function

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Fondaparinux Pharmacokinetics

• Rapidly completely absorbed following SQ
  administration
• Peak plasma concentrations in 2 hrs after a
  single dose 3 hrs with repeated once-daily
  dosing
• Elimination t½ 17 to 21 hrs
• Anticoagulant effect persists 2 to 4 days after
  discontinuation
• No known drug interactions

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Dosing Administration

• Fondaparinux FDA-approved indications
• VTE prophylaxis following orthopedic surgery
• DVT/PE treatment
• VTE prevention 2.5 mg SQ once daily 6 to 8 hr
  after surgery
• lt 50 kg not indicated
• DVT or PE treatment 7.5 mg SQ once daily
• gt 100 kg 10 mg once daily
• lt 50 kg 5 mg daily

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Fondaparinux Monitoring

• No routine coagulation testing required
• Evaluate baseline CBC then periodically
• Baseline kidney function in patients at risk of
  developing renal failure
• discontinue if CrCl lt 30 mL/min

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Fondaparinux

• Safe in elderly patients
• however, major bleeding risk increases with age
• Pregnancy category B
• Not studied in pediatric populations
• Most common adverse effect bleeding
• risk related to weight
• use caution with epidurals

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Direct Thrombin Inhibitors (DTIs)

• Directly interact with thrombin
• Four parenteral agents lepirudin, desirudin,
  bivalirudin, argatroban
• Oral agents under investigation
• darbigatran etexilate in most advanced phase of
  clinical development
• ximelagatran not FDA approved due to concerns of
  hepatotoxicity

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Direct Thrombin Inhibitors

• Do not require antithrombin (cofactor) for
  antithrombotic activity
• Inhibit circulating clot-bound thrombin
• Do not induce immune-mediated thrombocytopenia
• used for HIT treatment
• Hirudin isolated from salivary secretions of
  medicinal leech (Hirudo medicinalis)

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DTI Lepirudin

• Irreversible thrombin inhibitor
• Continuous IV infusion or SQ administration
• Indications anticoagulation in patients with HIT
  associated thrombosis
• Monitor for bleeding
• Renal elimination adjust dose for renal
  impairment
• t½ 1.3 hr
• CrCl lt 15 mL/min hemodialysis elimination t½
  up to 2 days

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DTI Lepirudin

• Up to 60 of patients treated with lepirudin 10
  days develop antibodies
• may increase anticoagulant effect
• monitor aPTT with prolonged therapy
• do not treat more than once if antibodies develop
  
• reports of fatal anaphylaxis

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DTI Desirudin

• Not available in US
• SQ administration
• Used for VTE prophylaxis in patients undergoing
  elective hip surgery
• t½ 2 hours
• 80 to 90 renal elimination and metabolism
• 40 to 50 of dose excreted unchanged in urine
• reduce dose in moderate to severe renal impairment

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DTI Bivalirudin

• FDA approved indication patients with unstable
  angina undergoing percutaneous transluminal
  coronary angioplasty
• Reversible thrombin inhibitor transient
  antithrombotic activity
• t½ 20 to 30 min
• Monitoring
• ACT (Activated Clotting Time)
• aPTT

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DTI Argatroban

• Prophylaxis/treatment of thrombosis with HIT
• Anticoagulation in patients with HIT or high risk
  for HIT undergoing percutaneous coronary
  intervention
• Inhibits clot-bound soluble thrombin
• t½ 39 to 51 minutes
• dose adjustment required for hepatic impairment
• Monitoring
• aPTT
• ACT

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Direct Thrombin Inhibitors

• Alterations in renal function may prolong
  lepirudin, desirudin, bivalirudin activity
• Drugs that inhibit liver enzymes may interact
  with argatroban
• Concurrent use of DTIs thrombolytic agents
  increases bleeding risk
• Adverse effects
• serious hemorrhage
• minor bleeding
• no agents to reverse DTI activity

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Warfarin

• Most prescribed anticoagulant in North America
• Anticoagulant of choice for long-term/extended
  anticoagulation
• FDA-approved indications
• VTE prevention treatment
• prevention of thromboembolic complications
  associated with atrial fibrillation, heart valve
  replacement, MI
• Requires continuous monitoring patient
  education
• narrow therapeutic index
• many food drug interactions

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Warfarin

• Inhibits enzymes responsible for cyclic
  interconversion of vitamin K in the liver
• No direct effect on previously circulating
  clotting factors or previously formed thrombi
• Time to pharmacologic effect dependant on the
  elimination t½s of coagulation proteins
• full antithrombotic effect achieved 8 to 15 days
  after initiation of therapy
• Prevents formation propagation of thrombi by
  suppressing clotting factor production

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Warfarin Pharmacokinetics

• Racemic mixture of R S isomers
• S isomer 2 to 5 times more potent than R isomer
• Rapidly extensively GI absorption
• peak plasma concentration 90 minutes
• PO bioavailability gt 90
• Both isomers 97 to 99 albumin bound
• Metabolized via hepatic cytochrome P450 (CYP)
  1A2, 2C9, 2C19, 2C8, 2C18, 3A4
• Large interpatient differences in dose
  requirements

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Dosing Administration

• Patient-specific dose based on desired intensity
  of anticoagulation patients response
• regular clinical laboratory monitoring
• Acute VTE UFH, LMWH, or fondaparinux should be
  overlapped with warfarin for gt 5 days
• INR checked every 3 to 5 days until stable
• Dose changes should not be made more than every 3
  days
• adjust by reducing or increasing calculated
  weekly dose

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Clinical Controversy

• Warfarin starting dose
• when started at 5 mg daily patients typically
  achieve therapeutic INR in 4 or 5 days
• some clinicians prefer to start at 10 mg or 15 mg
  daily with adjustments based on patient response
• patients reach therapeutic INR average of one day
  sooner
• allows earlier hospital discharge LMWH
  discontinuation
• bleeding complications may occur more frequently

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Clinical Controversy

• One study compared 5 mg 10 mg initial dose in
  patients with atrial fibrillation
• 10 mg dose
• faster response
• many patients became excessively anticoagulated
• Another study in acute venous thrombosis patients
• 10 mg initial dose safe with appropriate
  monitoring

Kovacs MJ, Rodger M, Anderson DR, et al.
Comparison of 10-mg and 5-mg warfarin initiation
nomograms together with low-molecular-weight
heparin for outpatient treatment of acute venous
thromboembolism. A randomized, double-blind,
controlled trial. Ann Intern Med
2003138714719. 
Crowther MA, Ginsberg JB, Kearon C, et al. A
randomized trial comparing 5-mg and 10-mg
warfarin loading doses. Arch Intern Med
19991594648
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Clinical Controversy

• Pharmacogenomics warfarin metabolism
• FDA issued labeling change in 2007 advising
  physicians to consider use of genetic tests to
  determine initial warfarin dose
• Genetic polymorphisms result in dose variability
  ? increased sensitivity or resistance
• CYP450 2C9 (metabolic clearance of warfarin)
• VKORC1 Vitamin K epoxide reductase complex
  subunit 1 (target enzyme for warfarin)
• Up to 2/3 Caucasians, 90 of Asians express at
  least 1 variant

FDA Approves Updated Warfarin Prescribing
Information. www.fda.gov/bbs/topics/NEWS/2007/NEW
01684.html Accessed 5-24-09. Kangelaris KN, Bent
S, Nussbaum RL, et al. Genetic testing before
anticoagulation A Systematic review of
pharmacogenetic dosing of warfarin. J Gen Intern
Med 200924(5)656-64. Rettie AE, Tai G. The
pharmacogenomics of warfarin. Molec Interv
20066223-227.
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Warfarin Adverse Effects

• Bleeding/hemorrhagic complications
• GI tract most frequent site
• intracranial hemorrhage most serious
• Warfarin-induced skin necrosis
• Purple-toe syndrome

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Warfarin Management

• Mildly elevated INR (3.5 to 5.0) reduce dose or
  hold 1 or 2 doses
• PO or IV vitamin K for swift reductions
• INR 5 to 9 hold warfarin low dose vitamin K
• Serious/life-threatening bleeding
• IV vitamin K
• fresh frozen plasma
• clotting factor concentrates
• recombinant factor VII

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Warfarin Interactions

• Vitamin K-containing foods
• stress dietary consistency, moderation
• Drugs that inhibit or induce CYP2C9, 1A2, 3A4
• Protein-binding displacement interactions
• transient changes
• Drugs that alter hemostasis, platelet function,
  or clotting factor clearance

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Warfarin Special Populations

• Pregnancy category X
• fetal hemorrhage
• teratogenic complications
• CNS abnormalities
• Can be used after week 10 or 12 of pregnancy but
  should stop 2 to 3 weeks before delivery to
  reduce risk of hemorrhagic complications
• Safe to use while breast-feeding

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Warfarin Special Populations

• Patients undergoing procedures
• generally not discontinued for minimally invasive
  procedures (dental work)
• higher-risk procedures stop 4 to 5 days prior

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General Approach to Periprocedural
Anticoagulation Therapy Management
aWarfarin stopped on day 5 if INR drawn on day
7 to 10 is 2.0 to 3.0 or day 6 if INR drawn on
day 7 to 10 is 2.5 to 3.5. bLMWH is initiated
2 days (36 to 48 hours) after warfarin is
discontinued. cProphylactic dose LMWH may be
used in low bleeding-risk procedures. dFull
(treatment) doses of LMWH can be resumed on days
1, 2, and 3 once hemostasis is adequate.
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
79
Venous Thromboembolism

• ASA not recommended for VTE prophylaxis
• LMWHs fondaparinux effective as prophylaxis
• no evidence one LMWH is superior to another
• UFH efficacious and cost-effective
• Warfarin commonly used for VTE prophylaxis
  following lower extremity orthopedic surgery
• Nonpharmacologic strategies
• ambulation, graduated compression stockings
• intermittent pneumatic compression (IPC) devices
• inferior vena cava (IVC) filters/Greenfield
  filters

80
VTE Special Populations

• Pregnancy
• UFH and LMWH preferred during pregnancy
• LMWH recommended over UFH
• avoid warfarin during first trimester
• crosses placenta
• can produce fetal bleeding, CNS abnormalities,
  embryopathy
• Pediatrics
• UFH warfarin used most frequently in pediatrics
• LMWH can also be used
• monitor antifactor Xa levels

81
VTE Special Populations

• Cancer patients
• VTE frequent complication of malignancy
• rate of recurrent VTE and risk of bleeding is
  much higher
• warfarin often complicated by drug interactions
  interruptions due to procedures
• LMWH lower incidence of bleeding
• continue anticoagulation as long as the cancer is
  active patient is receiving antitumor therapy

82
Clinical Controversy

• Evidence suggests LMWH administration for 3 to 6
  months after DVT/PE is more effective than
  warfarin in preventing recurrent VTE in cancer
  patients
• Current consensus guidelines recommend use of
  LMWH over warfarin for long-term VTE treatment
• many practitioners still prefer warfarin

83
Risk Classification and Consensus Guidelines for
Venous Thromboembolism Prevention
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
84
Risk Classification and Consensus Guidelines for
Venous Thromboembolism Prevention
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
85
Clinical Controversy

• Fondaparinux was superior to enoxaparin for VTE
  prevention in patients undergoing lower-extremity
  orthopedic surgery in phase III trials
• no difference in incidence of symptomatic PE
  death
• Long t½ of fondaparinux may increase bleeding
  risk
• cannot be reversed with protamine sulfate
• Some experts prefer fondaparinux
• asymptomatic DVTs PEs increase future risk of
  recurrent thrombotic events postthrombotic
  syndrome

86
Consensus Guidelines for Venous Thromboembolism
Treatment
aGrade of recommendation (1A, strong
recommendation applying to most patients without
reservation 1C, intermediate-strength
recommendation that may change when stronger
evidence becomes available 1C, strong
recommendation that applies to most patients in
most circumstances 2B, weak recommendation where
alternative approaches likely to be better for
some patients under some circumstances).
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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VTE Treatment

• UFH SQ or continuous IV infusion (preferred)
• LMWH
• Fondaparinux
• Warfarin not used for acute treatment of VTE
• anticoagulation effect not rapid
• high incidence of recurrent thromboembolism
• effective for long-term management
• Thrombolytic agents substantial risk of
  hemorrhage
• reserved for certain patients

89
Heparin-Induced Thrombocytopenia

• Serious adverse effect
• Severe thrombotic complications
• High morbidity mortality
• without treatment up to 50 of patients suffer
  complications or die in lt 30 days
• Diagnosis based on laboratory findings
• heparin antibody formation
• platelet activation
• 2 types non-immune-mediated heparin-associated
  thrombocyotpenia immune-mediated HIT

90
HIT Etiology

• HIT severe pathologic adverse effect of heparin
• typically begins at days 5 to 10 but can be
  delayed up to 2o days
• rapid-onset HIT occurs within 24 hrs
• platelets lt 150,000 mm3
• drop in platelet count gt 50 from baseline may
  indicate HIT
• frequency related to duration type of heparin
• increased incidence with IV full dose UFH than
  low dose SQ UFH or LMWH

91
HIT Pathogenesis

• Immunoglobulin mediated response to the heparin
  molecule ? platelet activation thrombin
  generation ? release of PF-4 ? PF-4 binds heparin
  ? stimulates IgG antibody production
• Heparin-PF-4-IgG complexes bind Fc receptor on
  platelets ? further platelet activation PF-4
  release
• PF-4 heparin-like molecules bind surface of
  endothelial cells ? cell damage tissue factor
  release

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HIT Clinical Presentation

• Thrombotic complications most common presentation
• DVT more common than PE
• arterial thrombosis less frequently
• Atypical manifestations
• skin necrosis
• venous limb gangrene
• anaphylatic-type reactions after UFH IV bolus

95
HIT Clinical Presentation
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
96
HIT Treatment

• Goal of therapy reduce thrombosis risk by
  decreasing thrombin generation and platelet
  activation
• Once HIT diagnosis is established or suspected,
  discontinue all sources of heparin
• initiate alternative anticoagulant
• Drugs of choice agents that rapidly inhibit
  thrombin activity are devoid of significant
  cross-reactivity with heparinPF-4 antibodies
• Warfarin recommended for long-term anticoagulation

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HIT Pharmacologic Treatment

• DTIs drug of choice for HIT thrombosis
• only lepirudin argatroban are FDA approved
• both considered equally suitable for initial
  treatment
• administered IV infusion
• titrated based on aPTT
• LMWHs not recommended
• 100 cross-reactivity with heparin-antibodies

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HIT Treatment

• Warfarin
• CI as monotherapy for initial HIT treatment
• initial rapid reduction of protein C ? increases
  risk of thrombosis in patients with HIT
• can be used for long-term anticoagulation
• Pregnancy
• limited evidence for DTI use
• lepirudin crosses the placenta
• fondaparinux may be an alternative

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HIT Therapeutic Outcomes

• Duration of treatment based on whether a
  thrombotic event occurred
• Thrombosis present alternative anticoagulant
  therapy followed by transition to warfarin after
  platelets recover to gt 150,000 mm3
• Avoid heparin for at least 3 to 6 months

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Acknowledgements

• Prepared By Amy Pai, Pharm.D.
• Series Editor April Casselman, Pharm.D.
• Editor-in-Chief Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA
• Chapter Authors Stuart T. Haines, Pharm.D., BCPS
• Daniel M. Witt, MD, FACP, FCCP
• Edith A. Nutescu, Pharm.D., FCCP
• Section Editor Robert L. Talbert, Pharm.D.,
  FCCP, BCPS, FAHA