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Review of Anticoagulants: Unfractionated heparin Low molecular weight heparins Warfarin. Stephanie Inverso Polli, Pharm.D. September 22, 2010. Objectives. Review the following related to unfractionated heparin (UFH), low molecular weight heparins (LMWH), and warfarin:

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Review of anticoagulants unfractionated heparin low molecular weight heparins warfarin l.jpg

Review of Anticoagulants:Unfractionated heparinLow molecular weight heparinsWarfarin

Stephanie Inverso Polli, Pharm.D.

September 22, 2010


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Objectives

Review the following related to unfractionated heparin (UFH), low molecular weight heparins (LMWH), and warfarin:

  • Pharmacology/ mechanism of action

  • Pharmacokinetics

  • Indications

  • Dosing

  • Contraindications

  • Adverse events

  • Monitoring


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Review of the Clotting Cascade


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Unfractionated and Low Molecular Weight Heparins


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UFH Mechanism of Action

  • Anticoagulant actions due to pentasaccharide structure found on UFH that binds to antithrombin (AT) causing a conformational change

  • This facilitates inactivation of thrombin (factor IIa) and factors Xa, IXa, XIa, XIIa

    • 18 polysaccharide units needed to inhibit thrombin

  • Inhibition of thrombin and factor Xa ultimately prevents fibrin formation

  • UFH does not inactivate clot bound thrombin

    • It prevents the existing clot from propagating and new clots from forming

Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S


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LMWH Mechanism of Action

  • Derived from unfractionated heparin

    • Final product is heterogeneous and about one-third of the size of original molecule

  • Contains the pentasaccharide sequence responsible for binding to antithrombin (AT)

  • Most LMWH molecules do not contain the required 18 polysaccharide units required to inhibit thrombin

  • LMWH primarily promote factor Xa inhibition, thus preventing fibrin formation

Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S


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UFH and LMWH: Comparison of Mechanism of Action

Weitz et al. N Engl J Med.1997;337:688-98.


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Pharmacologic Differences Between UFH and LMWH

*Subcutaneously


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Pharmacologic Differences Between UFH and LMWH Con’t


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Importance of Drug Characteristics- Case Review

  • Patient on enoxaparin 1mg/kg (100mg) q12 hours sub-Q for atrial fibrillation

  • Decision made to change to heparin drip

  • Enoxaparin administered at 0430

  • Enoxaparin discontinued at 0817 and heparin bolus 60 units/kg (6000 units)/ drip 12 units/kg/hr (1200 units/hr) ordered 0825 and started 0900

  • Heparin bolus and drip started 4.5 hours after enoxaparin dose


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Importance of Drug Characteristics- Case Review, continued

  • Several hours later patient became hypotensive requiring fluids and pressors

  • Retroperitoneal hemorrhage suspected and CT scan ordered

  • Patient coded and died before CT scan obtained

  • Retroperitoneal hemorrhage noted on autopsy


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Importance of Drug Characteristics- Case Review, continued

  • Heparin bolus and infusion started just after enoxaparin exerted its peak effect

  • Patient essentially received 2 full dose anticoagulants simultaneously

  • The heparin drip should have been started several hours after the enoxaparin without a bolus


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UFH Indications

  • Treatment and prevention of various venous and arterial thrombotic and embolic diseases


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UFH Prophylactic Dosing

  • Prophylaxis of venous thromboembolism (VTE)

    • 5000 units sub-q every 8 hours or every 12 hours

Geerts WH, et al. Chest.2008;13:381-453S.Kearon C, et al. Chest.2008;133:454-545S.

*Activated partial thromboplastin time


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UFH for Prophylaxis of VTE in Medical Patients

DVT

% patients

Greets WH, et al. Chest 2004;126:338-400S.


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UFH Treatment Dosing, Con’t

  • IV Treatment doses

    • VTE

      • 80 units/kg bolus

      • 18 units/kg/hour infusion

      • Titrated to aPTT

    • Acute coronary syndromes (ACS)

      • 60 units/kg bolus (maximum recommended initial bolus 4000 units)

      • 12 units/kg/hour infusion (maximum recommended initial infusion 1000 units/hour)

      • Titrated to aPTT

Kearon C, et al. Chest.2008;133:454-545S.Anderson JL, et al. JACC.2007;50:e1-e157.

Antman E, et al. JACC.2008;51:210-47.Raschke R, et al. Ann Intern Med. 1993;874-81.


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UFH Treatment Dosing, Con’t

Within first 48 hours

Within first 24 hours

  • Standard dose: 5000 units bolus; 1000 units/hr

  • Weight based dose: 80 units/kg bolus; 18 units/kg/hr

  • ¾ of patients in this study had VTE

aPTT result

aPTT result

P value for all comparisons < 0.001

Raschke R, et al. Ann Intern Med. 1993;874-81.


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UFH Treatment Dosing, Con’t

  • Sub-q treatment dosing

    • 5000 units IV bolus followed by 17,500 units sub-q every 12 hours or 250 units/kg sub-q every 12 hours

      • Titrate to aPTT*

    • 333 units/kg sub-q followed by 250 units/kg every 12 hours

      • Dose adjustments not done


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Cooper UFH Protocols

Several options available to allow for individualized patient care

  • Standard Dose No Bolus Target aPTT 67-101 seconds

    • 18 units/kg/hr

  • Standard Dose WITH BolusesTarget aPTT 67-101 seconds

    • Initial bolus: 80 units/kg

    • Initial infusion: 18 units/kg/hr

  • Low Dose No Bolus Target a PTT 67-84 seconds

    • Initial infusion: 12 units/kg/hr (may cap initial infusion dose for ACS)

  • Low Dose WITH BolusesTarget aPTT 67-84 seconds

    • Initial bolus: 60 units/kg (may cap initial bolus dose for ACS)

    • Initial infusion: 12 units/kg/hr (may cap initial infusion dose for ACS)

  • Vascular Surgery Post Op Target aPTT 40-52 seconds

    • 10 units/kg/hr

Note: aPTT reference ranges may change with each new lot of reagent (typically annually)


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FDA Approved Indications for LMWH


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LMWH Prophylaxis Dosing

  • Indications: VTE prophylaxis in medically ill patients, orthopedic surgery, abdominal surgery, trauma

  • Subcutaneous administration

Product information Lovenox 2007. Product information Fragmin 2007.


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LMWH Dosing, Con’t

  • Prophylaxis in medical patients

    • Enoxaparin 40mg sub-q daily

      • Has been compared directly to UFH in medically ill patients

      • Lower rates of DVT in certain patient populations with enoxaparin compared to UFH

        • Heart failure

        • Stroke

        • Respiratory disease

    • Dalteparin 5000 units sub-q daily

Product information Lovenox 2007. Product information Fragmin 2007. Shomaker, et al. Blood 1999. Leizorovicz, et al. Circulation 2004. Samama, et al. N EJM 1999.


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LMWH for Prophylaxis of VTE in Medical Patients

MEDENDOX Trial

P<0.001

% patients

Samama MM, et al. N Engl J Med 1999;341:793-800. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin


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LMWH for Prophylaxis of VTE in Medical Patients

PREVENT Study

% patients

Leizorovicz A, et al. Circulation 2004;110:874-79. SD= sudden death; VTE= venous thromboembolism; LMWH= low molecular weight heparin; Dalt= dalteparin


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LMWH vs. UFH for Prophylaxis of VTE in Medical Patients

TE Complications and death

% patients

P=0.04

Shomaker U, et al. Blood 1999;94 (supp1):399a. VTE= venous thromboembolism; Resp= respiratory

LMWH= low molecular weight heparin; HF= heart failure; Enox= enoxaparin;UFH= unfractionated heparin


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LMWH vs. UFH for Prophylaxis of VTE in Medical Patients

The PRIME Study- VTE

%patients

Lechler E, et al. Haemostasis 1996;26 (suppl 2):49-56. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin


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LMWH vs. UFH for Prophylaxis of VTE in Medical Patients

PRINCE Study- VTE

%patients

Kleber FX, et al. Am Heart J 2003;145:614-21. VTE= venous thromboembolism; Resp= respiratory

LMWH= low molecular weight heparin; HF= heart failure; Enox= enoxaparin;UFH= unfractionated heparin


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LMWH vs. UFH for Prophylaxis of VTE in Medical Patients

PRINCE II Study- VTE

%patients

Kleber FX, et al. Circulation 1999;100 (suppl 18):I-619. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin


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LMWH vs. UFH for Prophylaxis of VTE in Medical Patients

Bleeding

%patients

Shomaker U, et al. Blood 1999;94 (supp1):399a. Lechler E, et al. Haemostasis 1996;26 (suppl 2):49-56. Kleber FX, et al. Am Heart J 2003;145:614-21. VTE= venous thromboembolism; LMWH= low molecular weight heparin; Enox= enoxaparin; UFH= unfractionated heparin


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LMWH Dosing, Con’t

  • Treatment of VTE

    • Enoxaparin

      • Outpatient DVT 1mg/kg sub-q twice daily

      • Inpatient DVT ± PE 1mg/kg sub-q twice daily or 1.5mg/kg sub-q daily

    • Dalteparin (off label use)

      • 100 units/kg sub-q twice daily

    • Tinzaparin

      • Inpatient DVT ± PE 175 units/kg sub-q daily

    • All in conjunction with warfarin until goal INR achieved

Product information Lovenox 2007. Product information Fragmin 2007. Product information Innohep 2007. Kearon, et al. JAMA 2006.


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LMWH Dosing, Con’t

  • Extended treatment of VTE in patients with cancer

    • Enoxaparin (off label use)

      • 1.5 mg/kg sub-q daily for 3 months

    • Dalteparin

      • 200 units/kg (up to 18,000 units) sub-q daily for 1st month

      • 150 units/kg ( up to 18,000 units) sub-q daily months 2-6

Product information Fragmin 2007. Meyer, et al. Arch Int Med.2002. Lee, et al. NEJM.2003.


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LMWH versus UFH for Treatment of DVT

  • Compiled results from several studies

  • Mortality benefit with LMWH limited to those with cancer

Kearon C, et al. Chest.2008;133:454-545.


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LMWH Dosing, Con’t

  • Acute coronary syndromes/ myocardial infarction

    • Enoxaparin

      • NSTE ACS 1mg/kg sub-q twice daily

      • STEMI 30mg IV bolus followed by 1mg/kg sub-q twice daily (max 100mg for first 2 doses)

        • If 75 years or older, no IV bolus and 0.75 mg/kg sub-q twice daily (max 75 mg for first 2 doses)

    • Supplemental dosing in PCI

      • Enoxaparin 0.3mg/kg IV if last sub-q dose was greater than 8 hours prior to balloon inflation

    • Dalteparin

      • NSTE ACS 120 units/kg (up to 10,000 units) sub-q twice daily

Product information Lovenox 2007. Product information Fragmin 2007.


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LMWH Renal Dosing Adjustments

  • Clearance of LMWH decreased in patients with renal impairment resulting in increased risk of bleeding

  • No clear dosing adjustment recommendations for dalteparin or tinzaparin

  • Enoxaparin for patients with creatinine clearance less than 30 ml/min

    • Prophylactic doses 30 mg sub-q daily

    • Treatment doses 1 mg/kg sub-q daily

  • Consider LMWH (anti Xa) level monitoring if used in patients with severe renal impairment

Product information Lovenox 2007. Sanderink, et al. Throm Res. 2002. Hirsh, et al. Chest. 2008;133;141-59S.


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LMWH Renal Dosing Adjustments, con’t

Participants received enoxaparin 40mg daily x 4 days

Sanderink, et al. Throm Res. 2002


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LMWH Dosing in Obese Patients

  • Significantly obese patients not well studied

  • Use actual weight for weight based dosing

  • May need higher prophylactic doses in significantly obese patients

  • Consider anti-Xa monitoring if used in patients with morbid obesity

Hirsh, et al. Chest. 2008;133:141-59S. Geerts WH, et al. Chest.2008;133:381-453.


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LMWH Dosing in Obese Patients, con’t

Participants receives enoxaparin 1.5mg/kg daily x 4 days

Sanderink, et al. Clin Pharm Ther. 2002


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UFH and LMWH Contraindications

  • Active bleeding

  • Heparin induced thrombocytopenia

  • Hypersensitivity to pork products

  • Hypersensitivity to heparin (all LMWH)

  • Hypersensitivity to benzyl alcohol (LMWH multi-dose vials)


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Warning: Neuraxial Anesthesia

  • Patients receiving neuraxial anesthesia are at high risk for developing epidural hematomas when given LMWH; no increased risk with low dose UFH sub-q

  • LMWH should be held at least 12 hours prior to removal of epidural catheters

  • LMWH may be restarted at least 2 hours after spinal needle/ epidural catheter is removed

Product information Lovenox 2007. Product information Fragmin 2007. Product information Innohep 2007. Horlocker TT, et al. Reg Anesth Pain Mad.2003;28:172-97. Geerts WH, et al. Chest.2008;133:381-453S.


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UFH and LMWH Adverse Events

  • Bleeding

    • Can occur at any site (GI, intracranial, retroperitoneal, urinary tract, etc)

    • Ecchymosis/ hematomas common at sub-q injection sites

    • Risk increases with concurrent antithrombotic drugs, recent surgery, trauma, invasive procedures, concomitant hemostatic defects

Hirsh, et al. Chest.2008;133:141-159S.


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UFH and LMWH Adverse Events, Con’t

  • Heparin Induced Thrombocytopenia (HIT)

    • Immune mediated platelet activation

    • Life and limb threatening hypercoagulable disorder

    • Platelets decrease to 50% of baseline or less than 100,000

    • Must discontinue all forms of UFH or LMWH (including flushes and UFH coated catheters)

    • Less common with LMWH, but chance of cross-reactivity

    • Must treat with an alternate anticoagulant (argatroban or lepirudin followed by warfarin after platelet recovery)

Hirsh, et al. Chest.2008;133:141-159S Warkentin TE, et al. Chest.2008;340-80S.


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Thrombotic Complications of HIT


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UFH and LMWH Adverse Events, Con’t

  • Osteoporosis

    • UFH binds to osteoblasts releasing substances that activate osteoclasts

    • Activation of osteoclasts results in osteopenia and osteoporosis with long term therapy

    • Most commonly seen in pregnant women as they are unable to use oral anticoagulants

    • Binding to osteoblasts less with LMWH than UFH

Weitz et al. N Engl J Med.1997;337:688-98. Hirsh, et al. Chest.2008;133:141-159S.


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UFH Monitoring

  • Complete blood count (hemoglobin/ hematocrit/ platelets)

  • Signs and symptoms of bleeding, thrombosis, HIT

  • UFH (therapeutic doses)

    • aPTT 6 hours after initiation and each rate change (mean half-life is 1.5 hours)

    • Therapeutic aPTT range is based on heparin levels (anti Xa levels) 0.3-0.7 units/ml

    • Heparin levels (anti Xa Levels) may be used in patients with elevated baseline aPTT

Hirsh, et al. Chest.2008;133:141-159S.


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Changes to Laboratory Monitoring of Unfractionated Heparin Therapy

  • UFH is a highly variable medication with substantial inter- and intra-patient variability

  • UFH has a narrow therapeutic range and a high risk of adverse events

    • Bleeding when above range

    • Thrombotic events when below range

  • aPTT has been the standard monitoring parameter for patients receiving UFH as a continuous IV infusion or high sub-Q doses (therapeutic, not prophylactic doses)


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Limitations of aPTT

  • Indirect measure of heparin activity

    • Measures clotting time

  • No standard reference range for aPTT

    • Therapeutic ranges are institution specific

    • Wide variation in reference ranges

    • Changes with each new lot of reagent

    • Changes with different manufacturers of heparin


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Limitations of aPTT, continued

  • Has poor correlation with UFH levels

    • Heparin response curve run with each new lot of reagent or new UFH manufacturer

    • All results plotted and a line of best fit determines the therapeutic aPTT range based on UFH levels of 0.3-0.7 units/ml

  • Can be affected by several diseases, acute phase reactants (ie fibrinogen, factor VIII), and medications rendering aPTT useless for UFH monitoring in certain situations


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Cooper’s Heparin Response Curve September 2009


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What Will Change

Effective mid- fall (date to be determined) UFH levels will be used to monitor UFH continuous infusions and therapeutic dose sub-Q UFH


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Advantages to Using UFH Levels

UFH levels are a more direct way to measure the anticoagulant effect of UFH

aPTT is not reliable in some situations

Institutions using UFH levels have observed:

Fewer UFH dose adjustments (decreased nursing time)

Decreased frequency of blood draws (decreased nursing time; less patient discomfort)

More time in therapeutic range (the ultimate goal)


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Advantages to Using UFH Levels, continued

Heparin response curve will not need to be performed each time a new lot of reagent is utilized or each time the manufacturer of heparin changes

Decreased lab tech time

No need to update protocols and reference ranges each year or more frequently


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What will NOT Change

Baseline aPTT will still be obtained prior to starting UFH to assess for underlying coagulation abnormalities

Baseline and daily CBC will continue to be obtained

UFH protocol dosing adjustments and physician notification will not change

Timing of labs for heparin protocols will not change (6 hours after initiation, bolus, dose change)

aPTT will be used to monitor direct thrombin inhibitors (argatroban, lepirudin)

Procedural areas using ACT to monitor UFH will continue to use ACT (ie OR, cath lab)


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Format for UFH Protocols

Shown: standard dose with boluses


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LMWH Monitoring

  • Complete blood count (hemoglobin/ hematocrit/ platelets)

  • Signs and symptoms of bleeding, thrombosis, HIT

  • LMWH

    • Routine monitoring not recommended

    • Consider LMWH levels (anti Xa levels) in morbidly obese patients, patients with significant renal impairment, pregnant patients

Hirsh, et al. Chest.2008;133:141-159S.


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UFH and LMWH Reversal

  • Protamine sulfate

    • Protein derived from fish sperm that binds heparin and neutralizes its effect

    • Serious adverse events include anaphylaxis, allergic reactions, hypotension and bradycardia

      • May be minimized by slow administration

      • Increased risk for adverse events in patients with previous exposure to protamine (including protamine containing insulin), sensitivity to fish, or men who have had vasectomies

    • Each 1 mg of protamine reverses 100 units of UFH

    • Each 1 mg of protamine reverses 100 anti-Xa units of LMWH

      • Reversal of LMWH with protamine is incomplete as it does not bind to the low molecular weight fragments

Hirsh, et al. Chest.2008;133:141-159S.


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Warfarin


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Warfarin Mechanism of Action

  • Vitamin K is oxidized and reduced in a cyclic fashion while acting as a co-factor for gamma-carboxylation of glutamate residues on vitamin K dependent coagulation proteins (II, VII, IX, X)

  • Warfarin interferes with the activation of vitamin K dependent factors, thus decreasing their activation

  • Also inhibits carboxylation of proteins C and S (regulatory anticoagulant proteins) through the same mechanism

    • Potential to cause a prothrombotic state, usually at initiation of therapy

    • In normal circumstances this is not the dominant effect of warfarin

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6.


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Warfarin Mechanism of Action, Con’t

Ansell J, et al. Chest.2008;133:160-98S.


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Warfarin Pharmacokinetics

  • Racemic mixture of R and S isomers

    • The S isomer is 2-5x more potent than the R isomer

  • Rapidly and completely absorbed from the GI tract

  • Half-life 36-42 hours

  • Highly protein bound (primarily to albumin)

  • Metabolized by the cytochrome P450 (CYP) enzyme system

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6.


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Warfarin Pharmacodynamics

  • Optimal anticoagulant effect is not seen for several (usually 5-7) days due to long half-lives of factors X and II

    • Initial increase in INR is secondary to reduction of factor VII

    • Procoagulant state possible since half lives of proteins C and S and shorter that factors X and II

    • Overlap with heparin (or other parenteral anticoagulant) necessary in patients with active thrombosis or at high risk of thrombosis

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6. Haines ST, Zeolla, Witt DM. In DiPiro, et al. 6th edition.2005;389.


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Warfarin Indications and INR Targets

  • Treatment and prevention of various venous and arterial thrombotic and embolic diseases

  • INR range usually 2-3 (with target of 2.5) or 2.5-3.5 (with target of 3)

*Common indications-- not all inclusive


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Risk of Intracranial Hemorrhage in Outpatients

Hylek EM, Singer DE, Ann Int Med 1994;120:897-902


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Importance of INR control

The European Atrial Fibrillation Trial Study GroupN Engl J Med 1995; 333:5.


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Warfarin Contraindications

  • Active bleeding from any site or increased risk of bleeding associated with active ulcerations

  • Pregnancy

  • Spinal puncture for diagnostic or therapeutic procedures or local anesthesia

  • Recent surgery of central nervous system, eye, or trauma with large open surfaces

  • Bacterial endocarditis


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Warfarin Dosing: Initiation in Hospitalized Patients

*If baseline INR off anticoagulation is elevated, consider consulting hematology for monitoring recommendations

** Consider low starting dose protocol in the following patients: elderly (greater than 60 years of age), debilitated, malnourished, heart failure, liver disease, recent major surgery, concomitant therapy with medications known to potentiate the effects of warfarin

Modified from: Crowther MA, Harrison L, Hirsh J. Warfarin: less may be better [letter]. Ann Intern Med.1997 Aug;127:333.


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Warfarin Dosing: Continuation in Hospitalized Patients

  • Warfarin continuation in hospitalized patients needs to be considered on an individual basis

  • For those patients with a short stay and minimal changes in clinical status, diet, and/or interacting medications, consider continuation or re-starting therapy at the dose from home

  • For patients with prolonged hospital stay, significant changes in clinical status, diet, and/or interacting medications, consider re-starting with the initial therapy nomogram or with a lower dose than the patient took at home

  • Higher doses may be necessary in patients on medications known to decrease the effectiveness of warfarin


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Warfarin Monitoring: Inpatients

  • Obtain baseline INR in patients prior to starting warfarin

    • Ideally should have baseline before any anticoagulant is administered (including parenteral anticoagulants)

  • Daily INR

    • May change to every other day if INR is stable


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Warfarin Dosing- Outpatients

  • Initiate warfarin doses between 5 and 10 mg

  • Adjust based on INR response

  • Use lower starting doses (less than or equal to 5 mg) in patients at increased risk for bleeding

    • Elderly, debilitated, malnourished, heart failure, liver disease, recent surgery, medications known to potentiate warfarin


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Warfarin Monitoring- Outpatients

  • INR every few days until stable dose achieved

  • Increase interval in patients receiving stable dose

    • Maximum recommended interval is 4 weeks

    • May need more frequent monitoring in patients with unstable dose response

Ansell J, et al. Chest.2008;133:160-98S.


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Warfarin Adverse Events

  • Hemorrhagic

    • Can occur at any site (GI, intracranial, retroperitoneal, urinary tract, etc)

    • Highest incidence of bleeding in the first month after initiation

  • Non-hemorrhagic

    • Skin necrosis

      • Associated with protein C (and less commonly protein S) deficiency

    • Purple toe syndrome

      • Cholesterol microemboli released as a result of warfarin induced bleeding into atherosclerotic plaques (reversible with discontinuation)

    • Congenital abnormalities

      • Fetal hemorrhage

      • Fetal bone development abnormalities

Ansell J, et al. Chest.2008;133:160-98S.


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Purple Toe Skin Necrosis


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Warfarin- Pharmacokinetic Drug Interactions*

CYP 2C9 is the enzyme responsible for the metabolism of the S isomer of warfarin (the more potent isomer)

**Inducers attenuate the effect of warfarin

***Inhibitors potentiate the effect of warfarin

*Not all inclusive

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6


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Warfarin- Pharmacodynamic Drug Interactions

  • Increased risk of bleeding when used with warfarin

    • Platelet active medications

      • Aspirin

      • Non steroidal anti-inflammatory drugs

      • Clopidogrel

    • Drugs affecting vitamin K synthesis or clearance

      • Antibiotics (especially broad spectrum)

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6


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Warfarin-Nutrient Interactions

  • Vitamin K containing foods/ beverages

    • May attenuate response to warfarin

    • Patients should maintain consistent intake of vitamin K in their diets

  • Grapefruit juice

    • May potentiate the response to warfarin

    • Inhibits CYP3A4, the enzyme responsible for the R isomer of warfarin

  • Cranberry juice

    • May potentiate the response to warfarin

    • Mechanism is unclear

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6


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Warfarin-Herbal Interactions*

  • Little data exists for interactions between warfarin and herbal products

  • Herbal products that may potentiate warfarin

    • Ginko

    • Garlic

    • Dong Quai

  • Herbal products that may attenuate warfarin

    • Ginseng

    • St John’s Wart

*Not all inclusive

Ansell J, et al. Chest.2008;133:160-98S. Regal RE, Tsui V. P&T.2004;29:652-6


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Warfarin Pharmacogenetics

  • Pharmacogenetics plays a role in pharmacokinetics and pharmacodynamics of warfarin

  • Testing available to look for mutations in the gene coding for CYP 2C9 and the gene coding for vitamin K oxide reductase complex 1 (VKORC1) enzyme

  • Pharmacogenetic based initial dosing not currently recommended due to lack of data from randomized trials

Ansell J, et al. Chest.2008;133:160-98S.


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Warfarin Pharmacogenetics, Con’t

  • Mutations in the gene coding for CYP 2C9

    • Single nucleotide polymorphisms of gene

    • Alters the rate of metabolism of warfarin

      • More rapid initial effect, lower dose requirements, longer half-life

    • Reduced warfarin requirements if one or more polymorphisms present

  • Mutations in the gene coding for VKORC1 enzyme

    • Leads to a protein either sensitive or resistant to warfarin inhibition

    • Initial and maintenance doses will be affected

Ansell J, et al. Chest.2008;133:160-98S.


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Management of Supratherapeutinc INR During Warfarin Therapy

Consider changes in diet, medications, and overall health

*Reduction in INR is usually seen 24-48 hours after oral vitamin K administration. Subcutaneous administration is not recommended due to erratic absorption and unpredictable response. High doses of vitamin K may lead to warfarin resistance for 1 week or longer.

Ansell J, et al. Chest.2008;133:160-98S.


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Management of Supratherapeutic INR During Warfarin Therapy, Con’t

Consider changes in diet, medications, and overall health

FFP= fresh frozen plasma

rVIIa= recombinant factor VIIa

PCC= prothrombin complex concentrate (**not routinely stocked at Cooper)

Ansell J, et al. Chest.2008;133:160-98S.


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Perioperative Management of Patients on Warfarin

  • Elective/ scheduled surgery or invasive procedures

    • Discontinue warfarin 5 days prior to surgery

    • Restart warfarin 12-24 hours after surgery and when hemostasis is achieved

    • If INR is 1.5 or greater 1-2 days prior to surgery, administer vitamin K 1-2 mg orally

    • Bridge with unfractionated heparin or enoxaparin as indicated

  • Urgent reversal for surgery or invasive procedures

    • Administer vitamin K 2.5-5 mg orally or by slow IV infusion

    • For emergent reversal administer FFP, PCC in addition to vitamin K 2.5-5 mg by slow IV infusion or orally

  • Discontinuation of warfarin is not necessary for the following procedures

    • Minor dental procedures (co-administration of local oral hemostatic agent is recommended)

    • Minor dermatologic procedures

    • Cataract removal surgery

Douketis JD, et al. Chest.2008;133:299-339S.


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Peri-operative Bridging Therapy

  • Off label use

  • Little data available on bridging to warfarin with parenteral anticoagulation

  • Risk-benefit needs to be considered on an individual patient basis

  • *preferred

Douketis JD, et al. Chest.2008;133:299-339S.


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Fondaparinux Mechanism of Action

  • Factor Xa inhibitor

    • Not a LMWH, however mechanism is similar

    • Pentasaccharide sequence only

    • Only inhibits factor Xa

    • No effect on thrombin

Comp PC. Pharmacotherapy.2003;772-87.


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Fondaparinux Pharmacokinetics

  • Rapidly and completely absorbed after sub-q administration

  • Binds significantly to antithrombin, but not to other plasma proteins

  • Renally eliminated

  • Half-life 17-21 hours

Product information Arixtra 2008


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Fondaparinux Indications

  • Prophylaxis of VTE

    • Hip fracture surgery, including extended prophylaxis

    • Hip and knee replacement surgery

    • Abdominal surgery

    • Initial dose 6-8 hours after surgery

  • Treatment of

    • DVT

    • Inpatient PE

  • NSTE ACS/ STEMI (off label)

Product information Arixtra 2008.


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Fondaparinux Dosing

  • Prophylaxis of VTE after surgery

    • 2.5 mg daily

  • Treatment of DVT/ PE

    • Less than 50kg: 5 mg daily

    • 50-100kg: 7.5 mg daily

    • Greater than 100kg: 10 mg daily

  • NSTE ACS/ STEMI (off label)

    • 2.5 mg daily

All doses sub-q Product information Arixtra 2008. OASIS Investigators. NEJM. 2006. OASIS Investigators. JAMA.2006.


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Fondaparinux Contraindications

  • Creatinine clearance less than 30 ml/min

  • Weight less than 50 kg for surgical prophylaxis indications

  • Active bleeding

  • Endocarditis

  • Thrombocytopenia

    Warning

    • Epidural hematomas

    • Avoid using with continuous epidural analgesia; start at least 2 hours after catheter removed

Product information Arixtra 2008. Geerts WH, et al. Chest.2008;133:381-453S. Horlocker TT, et al. Reg Anesth Pain Mad.2003;28:172-97.


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