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Anticoagulant Management Program and Guidelines Oral Anticoagulants – Warfarin a. Target INR Goals by Disease States b. Dosing Protocol – Initiation of Warfarin c. Dosing Protocol – Adjusting Maintenance Dose d. Monitoring e. Warfarin Drug Interactions f. Use of Vitamin K for Reversal of Overanticoagulation g. Warfarin per Pharmacy Protocol a. UFH – Unfractionated Heparin b. LMWH – Enoxaparin c. Fondaparinux Introduction

The use of anticoagulants for acute inpatients introduces challenges not only because these agents are known to have a narrow therapeutic range, but also because there are patient variables and potential drug–drug interactions that can complicate its management. This guideline was developed to provide the clinician with a standardized protocol for these patients who require anticoagulation. The Pharmacy and Therapeutic Committee along with other stakeholders at the Ronald Reagan UCLA Medical Center have reviewed and approved the use of these guidelines. The guidelines are based on recommendations from the 2008 ACCP Evidence Based Clinical Practice Guidelines 8th ed. These Anticoagulation Management Guidelines should be used as a guide by all clinicians who are responsible for dosing and monitoring these anticoagulant agents. If the physician orders “Warfarin Dosing per Pharmacy”, the pharmacist shall also manage the warfarin therapy based on these standard guidelines. Warfarin

I. Mechanism of Action
a. Inhibits reduction of vitamin K epoxide, thereby limiting activation of vitamin K dependent clotting factors: II (prothrombin), VII, IX, X. Antithrombotic effect primarily due to reduction in prothrombin. b. Inhibits synthesis of anticoagulant proteins C and S (potential procoagulant II. Pharmacokinetics
a. Warfarin is a racemic mixture of two active isomers, R and S. The S-isomer is approximately five times more potent than the R-isomer. intravascular, highly protein bound (>98%) primarily to albumin; only free drug is pharmacologically active. d. Half-life: 36-42 hours e. Time to steady state = approximately 10 days Factor II = 60 hrs Factor VII =6 hrs Factor IX = 24 hrs Factor X = 40 hrs NOTE: Anticoagulation may be seen within 24 hours due to inhibition of Factor VII, but peak anticoagulant activity is delayed for 72-96 hours due to Factor II inhibition (2-3 days after 1st therapeutic INR) f. Metabolism: Hepatic microsomal enzymes to inactive metabolites - S-isomer is metabolized primarily by cytochrome P450 (CYP) 2C9 - R-isomer is metabolized by CYP 1A2 and CYP 3A4 *Of note: Since S-isomer is much more potent than R-isomer, medications that inhibit or induce P450 2C9 lead to the most significant drug interactions. - Reduce dose with hepatic dysfunction and with hypermetabolic states (increased catabolism of vitamin-K dependent factors) - Not significantly affected by dialysis III. Optimal Therapeutic INR Goals by Indication and Duration of Anticoagulation
Indication
Duration/Comments
Atrial Fibrillation (AF)/ Atrial Flutter
(risk factors: age>75; HTN, diabetes, CHF or LV dysfxn) With prior history of stroke/TIA/systemic embolism Pre-cardioversion (afib/aflutter > 48h) Ischemic Stroke
Cause of stroke or TIA: Afib/Cardiomyopathy Myocardial Infarction (MI)
Following myocardial infarction in high risk patients (High risk: ant. MI, sign. HF, intracardiac thrombus, Thromboembolism (DVT/PE) ** with concurrent UFH/LMWH/Fondaparinux for at least 5 days and until INR > 2 for >24h
Treatment/prevention of recurrence
Chronic thromboembolic pulmonary hypertension Spontaneous superficial vein thrombosis Valvular Disease
With recurrent TIA despite aspirin therapy With AF, hx systemic emb, LA thrombus, LA >55mm Valve Replacement – Bioprosthetic
With additional risk factors for thromboembolism Valve Replacement – Mechanical
Medtronic Hall tilting disk in NSR w/ nl LA size Caged ball or caged disk (aortic or mitral) With additional risk factors for thromboembolism (AF, LA enlargement, hypercoagulable condition, Reference: Antithrombotic and Thrombolytic Therapy: ACCP Evidence Based Clinical Practice Guidelines, 8th ed. 2008 IV. Dosing
The warfarin dose that is required is variable and dependent on a number of patient-specific and environmental factors. Evaluate patient to determine warfarin sensitivity* and use guidelines below for initial dosing. Warfarin
Warfarin
Warfarin
Moderate
Sensitivity*
Sensitivity*
Sensitivity*
Make adjustment based on total weekly dose (increase or decrease) by 5-20% depending on current INR and target INR Malnourished Malabsorption syndrome/ chronic diarrhea Cancer Hypoalbuminemia (<2) Thyrotoxicosis Genetic polymorphism of CYP450 2C9 b. Maintenance Warfarin Dosing Guidelines The following chart should be used as a guideline to adjust therapy for patients already receiving warfarin. For Target INR 2.0 – 3.0
INR< 2.0
INR 2.0 – 3.0
INR 3.1 – 3.5
INR 3.6 – 4.0
Hold 0 -1 dose; then decrease weekly dose by 10-15% INR >4.0
Hold dose until INR therapeutic; assess bleeding risk, +/- Vitamin K administration; decrease weekly dose by 10-20% - See chart* * Guidelines on Vitamin K1 Administration for Reversal of Warfarin

For Target INR 2.5 – 3.5
INR< 2.5
INR 2.5 – 3.5
INR 3.6 – 4.0
INR 4.1 – 5.0
Hold 0 -1 dose; then decrease weekly dose by 10-15% INR > 5.0
Hold dose until INR therapeutic; assess bleeding risk, +/- Vitamin K administration;; decrease weekly dose by 10-20% - See chart* * Guidelines on Vitamin K1 Administration for Reversal of Warfarin
V. Monitoring
a. Baseline INR is recommended prior to initiating warfarin therapy to assess b. An INR within the last 48 hours is acceptable as a current baseline INR. c. Patients shall be carefully monitored with each dose and adjustments in dose are d. With initial dosing, the INR will usually increase within 24- 36 hours. e. Daily INR should be obtained in hospitalized patients being initiated on warfarin until INR is within the desired therapeutic range, then INR can be evaluated twice weekly. f. Potential drug-drug and drug-disease state interactions shall be monitored and assessed with warfarin dose adjustments as needed. VI. Potential Warfarin Drug Interactions
Clinically Significant Interactions with Warfarin by Drug Class and Level of Causation
Potentiation of Warfarin Effects
Causation
probable
Probable
Possible
Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfain and its drug and food interactions. Arch Inter Med. 2005; 165; 1095-106. Inhibition of Warfarin Effects
probable
Probable
Influenza vaccine MVI supplement Raloxifene HCL Possible
Holbrook AM, Pereira JA, Labiris R, et al. Systematic overview of warfarin and its drug and food interactions. Arch Inter Med. 2005; 165; 1095-106. VII. Guidelines on Vitamin K Administration for Reversal of Warfarin
a. The peak effect of vitamin K on reversing warfarin anticoagulation occurs after 24 hours although initial effects will be noted within 6-12 hours of vitamin K dose. b. FFP replaces depleted clotting factors and therefore begins to work immediately c. If rapid reversal of an elevated INR is needed for emergent invasive procedures (i.e. surgery), administration of vitamin K and/or FFP may be required. INR should be rechecked in 12 hours. If still not at goal INR, repeat doses of Vitamin K and FFP may be required. d. Consider the patient’s future anticoagulation needs when planning the reversal of warfarin anticoagulation.

Guidelines on Vitamin K1 Administration for Reversal of Warfarin
INR Action/Recommendation
INR above target, but <5 with no
Continue with lower warfarin dose, OR omit a dose and significant bleeding
5-9 (no significant bleeding)
Omit 1 or 2 doses, monitor INR and resume therapy at a lower dose when INR therapeutic If patient at risk+ for bleeding
Omit a dose and administer vitamin K 1.25 – 2.5mg po 5-9 (rapid reversal required for
Administer vitamin K 2.5 mg po (INR to normalize in urgent surgery*)
24hrs); if INR still elevated, administer additional vitamin K 1.25 – 2.5 mg., consider giving FFP If NPO, may give Vitamin K 1mg IVPB over 30mins >9 (no significant bleeding)
Hold warfarin therapy AND administer vitamin K 5-10 mg PO, administer additional vitamin K in 24-48 hours if necessary; resume therapy at a lower dose when INR therapeutic Serious bleeding at any
Hold warfarin therapy AND administer vitamin K 10 mg by slow IV infusion over 30mins. diluted in D5W or NS; INR value
may repeat every 12 hours if needed. (Supplement with FFP, rFactor VIIa, Prothrombin Complex Concentrate, depending on urgency) Life threatening bleeding
Hold warfarin therapy AND supplement with FFP, rFactor VIIa, Prothrombin Complex Concentrate AND administer vitamin K 10 mg by slow IV infusion (1mg/min) diluted in D5W or NS. + Risk factors for bleeding: history of GI bleed, hypertension, cerebrovascular disease,
ischemic stroke, congestive heart failure, renal insufficiency, concurrent aspirin, age
>75, and recent major surgery
*Note if INR >1.5 but < 5 requiring reversal for urgent surgery, administer vitamin K
1.25 mg – 2.5mg PO, or for patients NPO, 1mg IV over 30mins.
Warfarin Per Pharmacy Protocol
a. Pharmacists who have been trained for warfarin per pharmacy and have passed the appropriate competency tests may assume the responsibility of dosing and monitoring warfarin therapy if the physician orders “warfarin per pharmacy”. b. Baseline and daily INRs shall be ordered and monitored by the pharmacists. c. Pharmacists utilize the Pharmacy and Therapeutics Committee approved “Anticoagulation Guidelines” for daily warfarin dosing. d. Doses shall be adjusted per RRUCLA standard warfarin dosing guidelines to e. Pharmacists shall notify the physician if any of the following occur: (1) the INR > 5 (2) for any clinically significant signs of thrombosis or bleeding are being (3) if they need clarification of the patient’s clinical status. f. Orders shall be written on the Anticoagulant Order form which will indicate the current INR, the target INR and the order for the warfarin dose. IX. Quality Assurance and Performance Improvement
Clinical patient outcomes shall be measured and documented to ensure the safe and effective use of anticoagulants under this anticoagulant management protocol. The following indicators shall be reviewed and tracked at least quarterly. Data shall be reported to the Medication Event and P&T Committee quarterly. a. Average time to therapeutic INRs b. % of INRs > 5 c. Adverse Heparin – Unfractionated (UFH)
I. Mechanism of Action
a. Binds to and causes conformational change in anti-thrombin III thereby accelerating inactivation of activated clotting factors IIa (thrombin), IXa, Xa, XIa and XIIa, subsequently halting coagulation. b. Low dose predominantly affects factor Xa (prophylaxis) c. Full dose predominantly affects factor IIa (thrombin) (established clot) II. Pharmacokinetics
Absorption (SQ): completely absorbed (at treatment doses); peak concentrations at 2-4 hrs c. Half-life: 90 minutes (range 0.5-2 hours) d. Mean time to steady state = 6 hours (3-5 half-lives) i. Increases with larger doses (non-linear) ii. Decreases with PE, massive thrombus, or new clot (increased clearance) e. Metabolism: degraded by reticuloendothelial system f. No dose adjustment necessary for hepatic III. Treatment (initial dosing)
a. Initial doses based on using actual body weight b. Use weight-based heparin protocol for dosing adjustments and monitoring i. Venous Thromboembolus (VTE)/Pulmonary embolism (PE) 1. UFH 80 units/kg (bolus), not to exceed 10,000 units 2. UFH 18 units/kg/hr (maintenance), max initial infusion rate 2,000 1. UFH 70 units/kg (bolus), not to exceed 5,000 units 2. UFH 15 units/kg/hr infusion (maintenance), max initial infusion rate of 1,000 units/hr, and titrate per protocol IV. Monitoring
a. Activated partial thromboplastin time (aPTT) b. Collect 6 hours after initiation or rate change of heparin infusion, adjust per V. Use of Protamine – Reversal of heparin
a. Binds to heparin forming a stable complex devoid of anticoagulant activity. b. Reserved for patients with clinically significant bleeding episodes while receiving heparin therapy. The drug is not indicated in cases of minor bleeding as withdrawal of heparin will generally result in correction of bleeding within several hours. c. Use with supportive care of the patient and possible transfusion therapy. d. Dosing - 1 mg of protamine will reverse approximately 100 units of heparin e. Initial doses rarely exceed 50 mg f. Infusion related adverse effects including hypotension and bradycardia can be minimized by extending the infusion time (10 minutes) g. Follow-up aPTT should be drawn 15 min post-dose to assess response Enoxaparin (LMWH)
I. Mechanism of Action
a. Low molecular weight heparin (LMWH) derived from porcine heparin with an average molecular weight of 4500 daltons. Both heparin and LMWH binds to and causes a conformational change in anti-thrombin III thereby accelerating inactivation of activated clotting factors. Due to its smaller size, enoxaparin preferentially inhibits factor Xa, with an anti-Xa:anti-IIa ratio of 3.6:1. II. Pharmacokinetics
a. Absorption (SQ): 90% absorbed by subcutaneous route b. Peak anti-factor Xa activity 3-5 hours after injection c. Distribution: Similar to intravascular volume d. Elimination is primarily renal e. Half-Life (based on anti-factor Xa activity): 6 hours (multiple doses) f. Prolonged in patients with renal insufficiency due to decreased clearance III. Dosing
c. Treatment Dosing: 1 mg/kg SQ bid* (Actual body weight) i. Prophylaxis dosing: Enoxaparin 30mg SQ daily ii. Treatment dosing: Enoxaparin 1mg/kg SQ daily NOTE: * 1 mg/kg SQ BID is preferred in following patients: proximal DVT, obese patients, hypercoagulable state, patients with increased bleeding risk IV. Monitoring
a. Serum Creatinine– as dose adjustments required with renal insufficiency. Use in patients with severe renal dysfunction will prolong elimination half-life and may increase bleeding risk. UFH is recommended for patients on dialysis or renal impairment patients with high risk for bleeding. b. Platelet counts – daily CBC with platelets while on enoxaparin c. Anti-factor Xa levels (LMWH level) not generally necessary, however may be considered in special populations such as obese or renal insufficiency (defined as Clcr < 30 ml/min) patients. Limited data are available that correlate a specific anti-factor Xa range to antithrombotic activity or bleeding risk. i. Collect peak concentration 3-5 hours after the subcutaneous dose ii. Enoxaparin should be at steady state to account for accumulation, iii. Therapeutic Range (peak concentration): 0.6-1 Unit/ml (1 mg/kg dosing) V. Reversal of Anticoagulant Effect
a. Protamine may be used although it will only partially (approximately 60%)
Fondaparinux
I. Fondaparinux is the synthetic anticoagulant that selectively inhibits factor Xa activity. II. It is well absorbed and peak plasma concentrations are achieved within 2-3 hours. III. Elimination half-life is 17-21 hours, which allows for once daily dosing. Note: anticoagulant effect can persist from 2 to 4 days after discontinuation of the drug IV. Fondaparinux is contraindicated in patient’s with severe renal dysfunction (Clcr V. Dosing is based on indication and patient weight.
Prophylaxis: Fondaparinux 2.5 mg SC q24
Treatment of VTE:
a. Fondaparinux 5 mg SC q24h if patient weight <50kg
b. Fondaparinux 7.5 mg SC q24h if patient weight 50 – 100kg
c. Fondaparinux 10 mg SC q24h if patient weight >100kg
Unstable angina/Non Q wave MI/ Cerebral Ischemia: Fondaparinux 2.5 mg SC q24h

VI. Monitoring
a. Routine monitoring of coagulation parameters is not required due to its b. Fondaparinux does not affect aPTT, or prothrombin time (PT). c. In high risk circumstances, monitor Factor Xa activity d. Renal function should be documented at baseline and then closely monitored during the course of therapy. If CrCl is less than 30ml/min, fondaparinux should be stopped. e. Monitor for signs and symptoms of bleeding. CBC should be monitored periodically to screen for occult bleeding. VII. Reversal of Anticoagulant Effect
a. Fondaparinux is not reversed by protamine and at this time no specific antidote is available to reverse its antithrombotic activity. b. Fresh Frozen plasma and factor concentrates should be given in the event of a Perioperative Management of Antithrombotic Therapy
Management of anticoagulation before and after invasive procedures requires careful, patient-specific evaluation of patient’s risk for bleeding associated with the surgical procedure as well as the risk of thromboembolism associated with the discontinuation of the anticoagulation. The following chart provides a guideline for managing the anticoagulation therapy during the peri-operative period. Thromboembolic
Bridge Therapy
For patients who require temporary interruption of warfarin therapy before surgery or a procedure and require normalization of INR for surgery/procedure. 2. Consider vitamin K 1 -2 mg orally if INR is still elevated (i.e. > 1.5) 1-2 days prior 3. Start full dose enoxaparin1 36 hours after last warfarin dose (> 2 days pre-op) 4. Stop enoxaparin 12 – 24 hrs prior to procedure (if on heparin can stop UFH 4-6 Post – Procedure: 5. Restart warfarin evening of procedure or post-op day 1 and when there is adequate hemostasis (based on physician/surgeon recommendations) a. High bleeding risk –start full dose enoxaparin1 24 hours after procedure b. Low bleeding risk– start full dose enoxaparin1 12-24hrs after procedure 2. Consider vitamin K 1 -2 mg orally if INR is still elevated (i.e. > 1.5) 1-2 days 3. Start low dose enoxaparin2 SC 36 hours after last warfarin dose (> 2 days pre- 4. Stop enoxaparin 12 – 24 hours prior to procedure Post – Procedure 5. Restart warfarin evening of procedure or post-op day 1 and when there is adequate hemostasis (based on physician/surgeon recommendations) a. High bleeding risk – no bridging OR start low dose enoxaparin2 12-24h b. Low bleeding risk– start low dose enoxaparin2 SC 12- 24hrs after procedure (consider full dose enoxaparin1) 1. Stop warfarin 5 days pre-op AND bridging not necessary (however, MD may consider low dose enoxaparin SC 36 hours after last warfarin dose) 2. Restart warfarin evening of procedure or post-op day 1 and when there is adequate hemostasis (based on physician/surgeon recommendations) 3. Consider low dose enoxaparin as a bridge 1 Full dose enoxaparin: 1 mg/kg SC BID or 1.5 mg/kg SC daily 2 Low dose enoxaparin: 30mg SC BID or 40mg SC daily Reference: ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2008; 133; (suppl).

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