D.16 USE OF ANTICOAGULATION THERAPY 36C24423R0132.pdf

Updated 01/25/18

Section 35 – USE OF ANTICOAGULATION THERAPY

35.1. PURPOSE: To establish the policy and procedures regarding initiation and monitoring of anticoagulation therapy for the VA Medical Center in Lebanon, Pennsylvania.

35.2. BACKGROUND:

A. Anticoagulants are commonly used to treat many cardiac and thromboembolic diseases acutely and chronically in both the inpatient and outpatient settings.

Incorrect use and medication misadventures associated with anticoagulants pose a significant risk to patient safety. Safe and effective use of this class of medications requires an evidence-based, systematic, multidisciplinary, and individualized approach to managing therapy.

B. This local policy and procedure was developed with input from members of pharmacy, medicine, specialty services, nursing, laboratory, and executive leadership in order to assure the development of safe anticoagulation practices for all Veterans treated with such therapies at this facility including the community based outreach clinics. The elements associated with the Joint Commission National Patient Safety Goal 3E have been used as guidance in conjunction with the latest Antithrombotic and Thrombolytic treatment guidelines from the American College of Chest Physicians (ACCP) to help assure that the highest level of standardized patient care is provided.

Definitions

Anticoagulation therapy: The term “anticoagulant” or “anticoagulation therapy” for the purpose of this document refers to all vitamin K antagonists (warfarin), heparin, low molecular weight heparin (eg. enoxaparin and dalteparin), factor Xa inhibitors (eg. fondaparinux), direct thrombin inhibitors (eg. argatroban), and direct-acting oral anticoagulants (dabigatran, apixaban, rivaroxaban).

Primary Care Provider: Refers to the patient’s VA assigned provider of Primary Care and may include Physicians, Nurse Practitioners, and Physician Assistants.

Ancillary Testing: Ancillary testing refers to laboratory services that are provided within the VA system, however outside of the physical setting of the main clinical laboratory.

Bridge Therapy: Bridge Therapy is the temporary use of a short and immediate-acting injectable anticoagulant during periods when the INR level is sub-therapeutic (e.g. when warfarin therapy is started) or when warfarin is being held in order to perform invasive procedures (peri-procedure management).

35.3. POLICY: The Lebanon, Veterans Affairs Medical Center will maintain a defined, standardized approach to anticoagulation management aimed at individualizing the care provided to each patient for the purpose of assuring safe and effective treatment with these agents across the continuum of care.

A. Dosing standards:

1. Intravenous Heparin: Must be administered as per facility approved weight based protocol, unless the clinical scenario clearly indicates that a more conservative approach is required. (Attachment A)

2. Low molecular weight heparin or Factor Xa inhibitors: Should be dosed based on recommendations that are consistent with the manufacturer and/or the latest treatment guidelines such as those available from the American College of Chest Physicians or the American College of Cardiology. Based on current treatment guidelines routine anticoagulation laboratory monitoring, such as anti-factor Xa levels, is not required for these agents. Provider may request to monitor anti-factor Xa levels in special population (i.e. obesity or renal impairment).

3. Oral vitamin K antagonists (warfarin): Although each patient will have different dosing requirements, the facility warfarin dosing and management protocols should be used as a guide for initiation and maintenance of therapy. This includes guidance on peri-procedural management. Clinical decisions regarding the care of a patient must be made on a case by case basis and the protocols are not intended to replace clinical judgment. (Attachment B)

4. Parenteral direct thrombin inhibitors (argatroban): Must only be dosed in accordance with facility approved HIT protocol. Unless the clinical scenario clearly indicates that a more conservative/alternative approach is required.

(Attachment C)

5. Direct-Acting Oral Anticoagulants (DOACS): Should be dosed based on recommendations that are consistent with the manufacturer and/or the latest treatment guidelines such as those available from the American College of Chest Physicians or the American College of Cardiology. Dabigatran should be stored in original container. Each dabigatran prescription shall include the following statement: “Must be Kept in Original Container – Discard 4 months after opening.”

B. Monitoring standards: The following defines the minimum required monitoring for patients receiving anticoagulation from this facility.

1. Recommended baseline and ongoing laboratory monitoring is suggested below. Further recommendations can be found in the protocol section:

(a) Warfarin

1. Baseline labs: PT/INR, CBC with platelets. Can consider hepatic function panel if clinically necessary.

2. Ongoing Labs: PT/INR, CBC with platelets will be measured at a minimum annually

3. For a patient to receive warfarin therapy, a current INR (ideally within 42 days) must be available.

(b) Injectable anticoagulants:

1. Heparin:

a) Baseline Labs: CBC with platelets, aPTT

b) Ongoing Labs: CBC with platelets periodically, aPTT

2. Low molecular weight heparin (LMWH):

a) Baseline Labs: current weight and serum creatinine

b) Ongoing Labs: serum creatinine and CBC with platelets periodically. In special circumstances, (i.e. obesity or compromised renal function), an anti-factor Xa level may be ordered.

3. Factor Xa Inhibitors (fondaparinux)

a) Baseline Labs: serum creatinine, CBC with platelets

b) Ongoing Labs: serum creatinine and CBC with platelets periodically

4. Direct Thrombin Inhibitor (Argatroban)

a) Baseline Labs: CBC with platelets, aPTT

b) Ongoing Labs: CBC with platelets periodically, aPTT

(c) Dabigatran (Pradaxa®)

1. Baseline labs: CBC, LFTs, serum creatinine

2. Ongoing Labs: CBC and serum creatinine to be monitored ideally within 3-6 months after initiation and every 6-12 months thereafter. LFTs should be monitored when clinically indicated (i.e. history of cirrhosis, liver disease)

3. Special Storage Instructions: Dabigatran must be stored in original container.

(d) Rivaroxaban (Xarelto®)

(e) Apixaban (Eliquis®)

(f) Edoxaban (Savaysa®)

2. Quality Assurance: Quality assurance information for anticoagulation management will be reviewed quarterly at P&T committee.

35.4. ACTION:

A. Chief of Staff, The Chief of Staff is responsible for ensuring a Medical Center Memorandum is developed that minimizes the risks of co-practice through providing warfarin as indicated only if the patient is willing to have their labs drawn through the Lebanon, VAMC and its associated outpatient clinics.

B. Associate Chief of Staff, Primary Care. The Associate Chief of Staff, Primary Care is responsible for ensuring:

1. Mid-level practitioners involved with anti-coagulation therapy have a scope of practice and/or utilize treatment protocols for anticoagulation therapy.

2. Competencies are established and assessed for mid-level practitioners that prescribe anticoagulation therapy.

3. Consistent approach to anticoagulation therapy is established for outpatient care as conducted by Primary Care Providers and that a Standard Operating Procedure for this is established.

C. Associate Chief of Staff, Medicine. The Associate Chief of Staff, Acute Care and Specialty Services is responsible for ensuring:

1. A process exists for discharge of patients who will be maintained on anticoagulation therapy aimed at assuring appropriate continuity of care is maintained and that patients are not lost to follow-up.

2. Mid level practitioners involved with anti-coagulation therapy have a scope of

3. Competencies are established and assessed for mid-level practitioners that

D. Associate Chief of Staff, Surgery. The Associate Chief of Staff, Surgery is responsible for ensuring:

1. A process exists for discharge of patients who will be maintained on anticoagulation therapy aimed at assuring appropriate continuity of care is maintained and that patients are not lost to follow-up.

2. Mid-level practitioners involved with anti-coagulation therapy have a scope of

3. Competencies are established and assessed for mid-level practitioners that

D. Chief, Pharmacy Services. The Chief, Pharmacy Services is responsible for ensuring:

1. Safe and timely dispensing of anticoagulation including:

a. Review of patients’ profile for any potential drug interactions or other such medication related concerns and notify providers of any potential problems.

b. Provide medication specific education and drug information to patients, their care givers, and other healthcare providers when requested.

c. Dispense medication in accordance with all facility policies and procedures for anticoagulation.

2. Only oral unit dose products, pre-filled syringes, or pre-mixed infusion bags for anticoagulant medications are dispensed for inpatients when available.

3. The number of concentrations and quantities of heparin vials stocked in patient care and procedural areas are limited to the minimum needed to meet patient care needs.

4. That all pharmacists complete initial required training regarding anticoagulation.

5. Anticoagulants are included on the Medical Center’s list of high-alert medications.

6. Multiple strengths or concentrations of the same anticoagulant stored in an automated dispensing device are stored in separate drawers and clearly labeled as high alert medications.

E. Laboratory Manager The Laboratory Manager is responsible for ensuring:

1. A critical INR value has been established.

2. A standard operating procedure has been established for communicating critical INR, PT, aPTT, and anti-Xa values.

3. Evaluation of turnaround time of outpatient INR results takes place and any opportunities for improvement are identified and implemented if appropriate.

4. Staff involved with ancillary testing and/or point of care testing are appropriately trained and evaluated for competency.

5. Staff involved with ordering labs for anticoagulation therapy are educated on applicable policies and procedures.

F. Chief, Nutrition and Food Service. The Chief, Nutrition and Food Service is responsible for ensuring:

1. A process is established to track or become notified of patients receiving meal services that are also receiving warfarin.

2. Warfarin is included in Nutrition and Food Service’s established food/medication interaction program and a standard operating procedure exists to ensure evaluation of all patients receiving meal services and warfarin.

G. ACNS, Acute Care. The ACNS, Acute Care is responsible for ensuring:

1. Assuring a method is established to train and assess competency for all nurses involved with the administration of the weight based heparin protocol.

2. Only programmable infusion pumps are used to infuse intravenous heparin.

3. Bar Code Medication Administration is appropriate utilized by staff to help assure safe use of anticoagulants.

4. Nursing staff completes required training in anticoagulation through education department

H. ACNS, Primary Care. The ACNS, Primary Care is responsible for ensuring:

1. A method is established to train and assess competency for all nurses involved in coordination of anticoagulation therapy for outpatients.

2. In conjunction with the Associate Chief of Staff, Primary Care; A Policy or Standard Operating Procedure exists that defines nursing services role in the coordination of anticoagulation therapy.

3. Nursing staff completes required training in anticoagulation through education department.

4. In conjunction with Laboratory Services assures that a standard operating procedure and competency assessment is developed for any nurses involved with point of care testing.

I. ACNS, Extended Care. The ACNS, Extended Care is responsible for ensuring:

1. Bar Code Medication Administration is appropriate utilized by staff to help assure safe use of anticoagulants.

2. Nursing assessments for patient receiving anticoagulation includes evaluating the patient for signs and symptoms of bleeding.

3. Nursing staff completes required training in anticoagulation through education department.

J. Designated Learning Officer. The designated learning officer is responsible for ensuring:

1. An educational course for healthcare providers (prescribers, nurses, pharmacists, and dieticians) is available for training.

2. Consistent patient/family education materials are available for use to all clinical services. Materials must include information on the importance of follow-up monitoring, compliance issues, dietary recommendations, and information regarding the potential for adverse reactions and drug interactions.

35.5. REFERENCES

A. The Joint Commission, 2009 National Patient Safety Goals; NPSG 03.05.01

B. National VA Hi-Alert Workgroup, Consensus Guidance to Insure the Safe Use of Anticoagulants.

C. VHA Medical Center Memorandum 20-58A Dual Care Policy

D. Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 feb;141(2 Suppl).

35.6. REISSUE DATE: May 2022

Section 35 - ATTACHMENT A Weight Based Heparin Protocol as directed in CPRS

Initial Dosing

Indication Initial Bolus Infusion Target Range Venous Thromboembolism

80Unit/kg bolus

18Unit/kg/h

72-116 seconds 0.3-0.7 IU/mL anti-Xa units

Coronary Thrombosis 60-70Unit/kg (Max: 5000 Units)

12-15Unit/kg/h (Max: 1,000 Units/h)

50-72 seconds 0.1-0.3IU/mL anti-Xa units

Coronary Thrombosis + fibrinolytic

60 Units/kg (Max: 4000 Units)

12 U/kg/h (Max: 1,000 Units/h)

Dosing Adjustments for Venous Thromboembolism PTT Bolus Dose Stop Infusion Rate Change Repeat PTT <40 80Units/kg +4Units/kg/hr 6 hours 40-71 40Units/kg +2Units/kg/hr 6 hours 72-116 Therapeutic No Change

6 hours If therapeutic x 2, may check next morning

117-124 -1Units/kg/hr 6 hours 125-145 Hold 60 min. -2Units/kg/hr 6 hours >145 Hold 120 min. -3Units/kg/hr 6 hours

Dosing Adjustments for Cardiac Indications PTT Bolus Dose Stop Infusion Rate Change Repeat PTT <35 2,500 units +2Units/kg/hr 6 hours 36-49 +2Units/kg/hr 6 hours 50-72

Therapeutic No Change

6 hours If therapeutic x 2, may check next morning

73-85 -1Units/kg/hr 6 hours 86-95 Hold 60 min. -2Units/kg/hr 6 hours >95 Hold 60 min. -3Units/kg/hr 6 hours

Weight Considerations: Whether actual bodyweight or a dosing weight should be used for obese patients receiving unfractionated heparin remains unclear. However, using actual bodyweight has been associated with excessive dosing regimens in obese patients.

At the same time limiting these doses could result in a delayed time to reach a therapeutic level. As such a dosing weight should be considered.

Dosing weight = ideal body weight + 0.3 [actual body weight – ideal body weight].

Ideal body weight(kg) = [(Ht. (in.) -60) x 2.3] + 50

The following chart may be used to guide initial therapy and is a more conservative approach for obese patients:

Weight Initial Bolus Initial Infusion Initial Infusion

(>70 yrs of age) Rebolus (Ptt <36)

Rebolus (Ptt 36-66)

40-49kg 3600Units 800Units/hr 700 3600Units 1800Units 50-59 4400Units 1000Units/hr 900 4400Units 2200Units 60-69 5200Units 1200Units/hr 1050 5200Units 2600Units 70-79 6000Units 1350Units/hr 1200 6000Units 3000Units 80-89 6500Units 1500Units/hr 1300 6500Units 3300 Units 90-99 7000Units 1600Units/hr 1400 7000Units 3500 Units 100-109 7500Units 1700Units/hr 1500 7500Units 3800 Units >110kg 8000Units 1800Units/hr 1600 8000Units 4000 Units

Recommendations for dose adjustments for a set rate are less effected by actual body weight because they are smaller changes. However for obese patients may wish to limit dose adjustments as follows:

4Units/kg changes to 350Units 3Units/kg changes to 250Units 2Units/kg changes to 200Units 1Units/kg changes to 100Units

Section 35 - ATTACHMENT B

Warfarin Outpatient Initiation

1. Intensity of anticoagulation should be guided by the latest treatment guidelines from the American College of Chest Physicians or other appropriate treatment guidelines. Risks of bleeding versus the benefits of anticoagulation must be considered prior to initiation of therapy for each patient.

2. Generally 5mg by mouth daily should be used for most patients: check INR every few days until stable. If the INR is rising rapidly, decrease the dose even if it is within the target range, and follow up within a clinically appropriate interval.

3. If dose needs adjustment; increase or decrease by 5-10% of the total weekly dose.

4. If INR is slightly out of range (example 0.5 or less), avoid dosage changes unless the clinical scenario dictates otherwise.

5. Consider using a lower initial dose (ex. 1-4mg) if age over 70, elevated baseline INR, malnourished, heart failure, liver disease, recent surgery, history of increased sensitivity to warfarin, or taking medications known to increase the anticoagulant effect of warfarin (ex.

Amiodarone).

6. Please note it should be remembered that vitamin K regardless of route will take ~24-48 hours for full effect.

Guidelines for warfarin follow-up

INR Warfarin Dose Repeat labs

Stable INR x 2 No change ~2 weeks Repeat stable INR after 2-3 weeks

No change Every 4 to 6 weeks provided remains stable

Target ± 0.5 (SINGLE out-of-range)

No change 1-2 weeks

INR > target, but less than 5

If due to transient cause (ex. diet) or minimal change in INR: no dosage change may be required More than nominal change: Withhold 1-2 doses, reduce dose by 5- 10%

5-7 days

5 ≤INR < 10,

NO significant bleeding

Withhold until INR within range (~1-3 doses), resume at lower dose with 10-

1-3 days

Updated 01/25/2018 2

20% reduction in total weekly dosage or as clinically indicated

10 ≥ INR,

NO significant bleeding

Withhold warfarin & give oral Vitamin K (2.5-5.0 mg), Resume at lower dose with 20-40% reduction in total weekly dosage when INR is therapeutic or as otherwise clinically indicated. This patient should be referred to the emergency department for appropriate assessment.

Refer to the Emergency Department

Serious bleeding at any elevation of

INR

Refer to Emergency Department

**= If phytonadione (vitamin K) is to be administered intravenously, dilute in 50mL of normal saline or dextrose solution and administer over 60 minutes. IV phytonadione is never given IV push.

Please note it should be remembered that vitamin K regardless of route will take ~24-48 hours for full effect.

Updated 01/25/2018 3

Guidelines for required interruption of warfarin therapy (Peri-Operative Management)

The following guidance should be utilized in patients undergoing procedures that will require interruption of anticoagulation therapy. Areas of uncertainty still exist and each patient should be assessed for the risk of bleeding versus their risk of thromboembolism to determine the optimal approach in each situation.

Risk Stratification for Peri-Procedural Interruptions of Warfarin “Bridging” with parenteral anticoagulants significantly increases the risk of bleeding, but has not been shown to reduce thromboembolic events. Given the lack of data indicating a net clinical benefit of bridging, the PBM-CPPO-Anticoagulation SME Workgroup suggests NOT bridging most patients. Bridging would generally not be recommended for low-moderate risk patients, as defined in the table below. Clinicians may consider bridging for high-risk patients, but bridging should not be considered automatic even for high-risk patients, and should always be decided on a case-by-case basis.

Indication for Anticoagulation Thromboembolic

(TE) Risk Mechanical Heart Valve Atrial Fibrillation

(AF)

Venous

Thromboembolism

(VTE)

High (>10% annual risk for TE)

•Any mitral mechanical valve

•Any mechanical valve with history of stroke, TIA, systemic embolism, or valve thrombosis occurring with prior interruption, or while on therapy

•Caged ball or tilting disc valve prosthesis

•CHADS2

1 score of 5-

6, if prior stroke was cardioembolic2

•Prior stroke, TIA, or systemic embolism in the last 3 months

•History of stroke, TIA, or systemic embolus occurring with prior interruption, or while on therapy

•Recent VTE within last 3 months

•VTE with anti-phospholipid syndrome

•VTE with active cancer3 for the following high thrombotic risk cancer types: pancreatic, CNS, GI, lung, endocrine, head/neck

•History or recurrent VTE during short-term interruption of anticoagulation therapy, in a patient planning to undergo a high thrombotic risk procedure

Low (<10% annual risk of TE)

•Any patient with mechanical heart valve, AF, or VTE not specified above

1 CHADS2 score is used over CHA2DS2-VASC as there is no data to support its use for perioperative risk stratification regarding bridge therapy. It is up to the discretion of providers to use CHA2DS2-VASC for risk stratification.

2 Prophylactic-dose LMWH is a reasonable choice for preventing venous thromboembolism in some patients, especially those whose risk-benefit balance is a close call. Prophylactic-dose LMWH would be an ineffective strategy to prevent arterial TE, and is not recommended in that context.

3 Active cancer is defined as ongoing treatment, treatment completed within the past 6 months, or palliative intent.

Updated 01/25/2018 4

Interruption of DOAC Therapy Prior to Surgery/Procedure

References:

1.) AE Burnett et al. Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis (2016) 41:206–232.

2.) Levy JH, Faraoni D, Spring JL, et al. Managing new oral anticoagulants in the perioperative and intensive care unit setting.

Anesthesiology 2013; 118:1466–1474.

3.) Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis 2013; 36:133–140.

4.) Wittkowsky AK. Novel oral anticoagulants and their role in clinical practice. Pharmacotherapy 2011; 31:1175–1191

Drug

Renal Function

Low Bleed Risk Surgery

(2 or 3 drug half-lives between last dose and surgery)

High Bleed Risk Surgery (4 or 5 drug half-lives between last dose and surgery)

Resumption of Therapy

Low Bleed Risk High Bleed Risk Dabigatran t½= 14-17 hrs

CrCl >50mL/min Last Dose: 2 days before procedure

Last Dose: 3 days before procedure

Resume on day after procedure (24 hrs post op.)

Resume 2-3 days after procedure

(48-72 hrs post op.)

Dabigatran t½= 16-18 hrs

CrCl 30-50 mL/min Last Dose: 3 days before procedure

Last Dose: 4-5 days before procedure

Rivaroxaban t½= 8-9 hrs

CrCl > 50 mL/min Last Dose: 2 days before procedure

Last Dose: 3 days before procedure

Rivaroxaban t½= 8-9 hrs

CrCl 30-50mL/min Last Dose: 2 days before procedure

Last Dose: 3 days before procedure

Rivaroxaban t½=9-10 hrs

CrCl 15-29 mL/min Last Dose: 3 days before procedure

Last Dose: 4 days before procedure

Apixaban t½= 7-8 hrs

CrCl > 50 mL/min Last Dose: 2 days before procedure

Last Dose: 3 days before procedure

Apixaban t½= 17-18 hrs

CrCl 30-50mL/min Last Dose: 3 days before procedure

Last Dose: 4 days before procedure

Edoxaban t½= 6-11 hrs

CrCL >50mL/min Last Dose: 2 days before procedure

Last Dose: 3 days before procedure

Updated 01/25/2018 5

Management of bleeding due to anticoagulation

Outpatients with major bleeding on any anticoagulant should be referred to the emergency department for appropriate management. The latest guidelines from the American College of Chest Physicians can be referenced if needed for appropriate management.

Idarucizumab (Praxbind) is a specific reversal agent for patients on Dabigatran (Pradaxa) when reversal of anticoagulant effects are needed in the following situations:

1.) Life-threatening or uncontrolled bleeding OR 2.) For emergency surgery/urgent procedures o Procedures that cannot be delayed at least 8 hours and where normal hemostasis is required

Dose: 5 grams (100 mL). Idarucizumab (Praxbind) is supplied as (two) 2.5 gram/50 mL vials; must administer BOTH vials for total of 5 gram dose.

• A quick order is available in CPRS when trying to order this medication:

Idarucizumab (Praxbind) for dabigatran (Pradaxa) REVERSAL

Antithrombotic Therapy and Prevention of Thrombosis, 9th Ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012 feb;141(2 Suppl). Available at: http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/Antithrombotic-Guidelines-9th-Ed http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/Antithrombotic-Guidelines-9th-Ed http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/Antithrombotic-Guidelines-9th-Ed

Updated 01/25/2018 6

Heparin-Induced Thrombocytopenia (HIT)

Treatment protocol

Initial procedure for suspected or confirmed HIT II:

Step 1 Consider calculating patients pre-test probability of HIT utilizing the 4T score

Discontinue all active heparin products (including heparin-bonded catheters, heparin flushes, or LMWHs). Post a sign at the bedside noting heparin allergy and label all IV sites or catheters with “No Heparin”.

Step 2 Obtain the Heparin-Induced Platelet Antibody (HIPA) with Reflex to Serotonin Release- Assay to aid in diagnosis.

Based on the following results of the HIPA assay, the following will occur:

1. If HIPA assay is negative (<0.4 OD), HIT diagnosis is unlikely. HIPA has a high negative predictive value. No further diagnostic testing will be performed.

2. If HIPA assay is equivocal or positive (≥ 0.4 OD), this will automatically reflex to perform Serotonin Release Assay (SRA) to confirm HIT diagnosis.

a. If SRA is negative, HIT diagnosis is excluded

a. If SRA is positive, HIT diagnosis has been confirmed.

Step 3 If HIT diagnosis confirmed or suspected, dedicate a central line to argatroban use only.

Obtain baseline aPTT and CBC with platelets.

Start argatroban infusion (refer to argatroban dosing protocol)

Updated 01/25/2018 7

ARGATROBAN DOSING PROTOCOL

Step 1

Draw patient’s baseline aPTT:_____ Target aPTT is 1.5 - 3 times baseline.

(Ref. range 42-84 seconds, baseline 28 seconds.)

Step 2

Calculate argatroban initial dose and infusion rate:

Patient’s actual body weight: ______kg Initial Rate 2mcg/kg/min: _____mcg/min continuous IV infusion (max dose 280mcg/min)

** consider starting with reduced infusion rate in certain special populations (see below)

Infusion rate: _____ml/hr – see table below (Standard concentration 250mg/250ml

0.9%NS)

**Special populations:

• Dose adjustments recommended in patients with decreased hepatic function, acute decompensated heart failure, multiple organ failure, severe anasarca or status post cardiac surgery.1

• Initial adjusted dose: 0.5 -1.2mcg/kg/min = ______mcg/min IV continuous infusion

Recommended Doses and Infusion Rates - Argatroban

Body Weight

(Kg)

Dose: 2mcg/kg/min Normal Hepatic Function

Adjusted Dose: 0.5mcg/kg/min Decreased Hepatic Function

Dose (mcg/min)

Infusion rate (ml/hr)

Dose (mcg/min) Infusion rate (ml/hr)

50 100 6 25 1.5 60 120 7.2 30 1.8 70 140 8.4 35 2.1 80 160 9.6 40 2.4 90 180 10.2 45 2.7

100 200 12.0 50 3.0 110 220 13.2 55 3.3 120 240 14.4 60 3.6 130 260 15.6 65 3.9 140 280 16.8 70 4.2

(Calculated table)

Step 3

Measure aPTT 2 hours after infusion is initiated. Repeat every 2 hours until the goal aPTT range is reached TWICE consecutively.

Adjust dose accordingly, keeping the steady state aPTT between 1.5-3.0 times the initial patient’s baseline value. For guidance on dose adjustments, refer to table below.

Do not exceed a dose of 10mcg/kg/min or aPTT of 100 seconds.

*Adjusted initial doses follows same algorithm.

Recommended Dose Adjustments in response to aPTT measurements:

aPTT value > 84 seconds Stop infusion for 2 hours; restart the infusion at 50% of the initial infusion rate. Check the aPTT in 2 hours after each dosage change aPTT value 42-84 second aPTT is at GOAL: No change in infusion aPTT value <42 seconds Increase the infusion rate by 20% and recheck aPTT in 2 hours after each dosage change. Repeat if still subtherapeutic. (do not exceed infusion rate of 10mcg/kg/min or aPTT value of 100 seconds) 5

Adapted from Susan Fugate and Julia Chiappe’s “Standardizing the management of heparin-induced thrombocytopenia” and The George Washington University Hospital’s IV Argatroban Protocol Orders

Updated 01/25/2018 8

Step 4 Check aPTT every 2 hours until the goal aPTT range is reached twice consecutively

Step 5 Once two consecutive aPTT ranges have been at goal, check aPTT daily, or indicate an alternative frequency if the risk of bleeding increased

Step 6 Monitor CBC, signs of bleeding.

Decreased liver function: Monitor CBC, signs of bleeding. Specify the type and frequency of liver function monitoring.

Discontinuation of Argatroban Therapy

Option 1: Transitioning to warfarin Option 2: NOT transitioning to warfarin Reduce the infusion rate gradually to achieve an aPTT value of approximately 42 seconds. (Follow guidance on next page.)

Discontinue Argatroban once platelet count recovers to over 100,000 plt/mcL

Transitioning to Warfarin After Argatroban

General Considerations:

• Do not use warfarin until platelet count has recovered to at least 150,000x109/L.1

• Concurrent therapy with argatroban and warfarin will result in falsely increased INR lab value -it does not cause a further reduction in vitamin K-dependent factor Xa activity than that would be seen with warfarin alone- for example INR of 4 on cotherapy does not have the same bleeding risk as INR of 4 on warfarin monotherapy.2

• INR should be corrected in patients on concomitant argatroban and warfarin therapy.2

• INR should be measured daily – argatroban should be discontinued if INR is 4 or higher.

Step 1 Start warfarin while continuing argatroban therapy. Maximum starting dose of warfarin should be 5mg daily. Consider lower starting dose (e.g. 2.5mg) in patients with hepatic impairment, heart failure or malnutrition. A loading dose of warfarin should not be used.1

Step 2 Measure INR daily.

Argatroban and warfarin cotherapy will cause a falsely increase INR value but will not result in additionally increased risk of a major bleed. Discontinue argatroban if INR > 4. Recheck INR in 4-6 hours, restart argatroban if when INR <4.

Step 3 Continue concomitant therapy with argatroban and warfarin for minimum overlap of 5 days AND until the platelet count has reached stable plateau AND the INR has reached the intended target.1

Step 4 Repeat INR in 4-6 hours after discontinuation of argatroban. 2

• If INR is within therapeutic range on warfarin alone, continue warfarin monotherapy.

• If INR is below the therapeutic range for warfarin alone, resume therapy with argatroban, Step 5 Once argatroban is discontinued, continue warfarin therapy. The length of warfarin therapy depends on whether patient has history of thrombosis.

• Patients without history of thrombosis – continue warfarin therapy for 4-6 weeks.

• Patients with history of thrombosis – continue warfarin therapy for 3-6 months.

References:

1.Warkentin TE; Greinacher A. Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2008 Sep;126(3 Suppl):311S-337S.

2.About Argatroban. Glaxo-Smith-Kline. Available via www.Argatroban.com on September 8, 2008 3.UpToDate database accessed September 10, 2008

4. Kiser TH, Burch JC, Klem PM, Hassell KL. Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy. 2008 Sep;28(9):1115-24.

Updated 01/25/2018 9

5. Fugate S, Chiappe J. Standardizing the Management of Heparin-Induced Thrombocytopenia. Am J Health Syst Pharm. 2008 Feb 15;65(4):334-9.

6. Watson, HG, Keeling, DM. The management of heparin-induced thrombocytopenia. Br J Haematol 2006; 135:269.

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