Perfusion Policies 101: Anticoagulation Reversal

Renee Toth, BS, CCP

 

Editor’s Note:

Renee is a colleague I work with quite often.  She is an amazing perfusionist as well as administrator, mom, and just a decent all around human being. She has a pretty scathing wit- so beware.  She offered to share a policy she has worked on for a quite awhile in a collaborative effort with some of her professional colleagues.  So I welcome you to read it and share it.  It is well written, and hopefully we shall add Renee to our editorial staff.

Enjoy 🙂

 

Anticoagulation Reversal Policy

Author:  Renee Toth, BS, CCP, (in collaboration with several colleagues)

 

Purpose:

Bleeding complications are a common concern with the use of anticoagulant agents.  In select situations, reversal of the effects of an anticoagulant may be desired.  This document provides guidelines for the reversal of anticoagulant agents in the setting of adult inpatients and ED patients.   

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General Terms & Information:

Minor bleeding

• Examples include: epistaxis, ecchymosis, menorrhagia, small amount of blood in stool, urine or oral cavity.

Non- major bleeding

• Bleeding with decline in Hgb of < 2 g/dL or requiring ≤ 1 unit of blood or packed cells.

Major bleed

• Acute major bleeding that includes one of the following: acute Hgb decline of ≥ 2 g/dL or acute bleeding requiring at least two units of blood or packed cells or symptomatic bleeding in a critical area organ (intracranial, intraocular, intraspinal, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome)⁴

Non-urgent reversal

• This includes most minor bleeding events and nonemergency surgeries where an intervention is needed (hip fracture, biopsies, etc.).  It is acceptable if reversal takes more than 12 – 24 hours.

Urgent reversal

• This includes non-major bleeding events that are not in a closed space and patient remains hemodynamically stable with supportive care.  It is acceptable if reversal occurs in 6 – 12 hours.

Emergent reversal

• This includes major or life-threatening bleeding or when emergent surgeries are required.  Immediate reversal is needed.

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PERSONNEL:

•  Nursing, Pharmacy Services, Medical Staff

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EQUIPMENT/FORMS:

• Not applicable

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PROCEDURE:

1. A summary of anticoagulants are listed in Appendix A

 

1. General management of anticoagulation-associated bleeding is based on the HASHTI principle
   1. Hold further doses of anticoagulant (or anti-platelet agent)
   2. Consider Antidote [e.g. Vitamin K, protamine, 4-factor Prothrombin Complex Concentrate (PCC), idarucizumab]
   3. Supportive treatment
      1. Volume resuscitation
      2. Inotropes as needed
      3. Optimize oxygenation
   4. Local or surgical Hemostatic measures
      1. Local or topical agents (fibrin glue, sealants, hemostatic agents, topical aminocaproic acid or tranexamic acid)
      2. Systemic hemostatic measures (intravenous tranexamic acid)
      3. Mechanical compression
      4. Standard suturing techniques
   5. Transfusion
      1. Red cells, platelets, FFP as indicated
   6. Investigate for bleeding source

 

1. Indications for the use of an anticoagulation reversal agent include the following³
   1. Life-threatening bleeding such as intracranial hemorrhage, symptomatic or expanding extradural hemorrhage, or uncontrollable hemorrhage
   2. Bleeding in a closed space or critical organ (intracranial, intraocular, intraspinal, retroperitoneal, intra-articular, pericardial, or intramuscular with compartment syndrome)
   3. Need for emergency surgery or intervention that is associated with a high risk of procedural bleeding (neurosurgery, lumbar puncture, cardiac or vascular surgery, hepatic or other major organ surgery)
   4. Need for surgery or invasive procedure associated with a high risk of bleeding that cannot be delayed to allow for drug clearance
   5. Patient is on warfarin and unable to tolerate the excess volume from an infusion of Fresh Frozen Plasma (FFP) (i.e. congestive heart failure)
   6. Strategies for reversal of antithrombotic agents in patients are summarized in Appendix B and Appendix C

 

1. Reversal of warfarin
   1. Non-urgent reversal
      1. Stop warfarin 5 days prior to procedure
      2. Check INR 1 – 2 days prior to procedure and consider vitamin K 1 – 2 mg PO if INR > 1.5
   2. Urgent reversal
      1. If procedure can be delayed 6 – 12 hours, give FFP and vitamin K 10 mg IV
      2. If procedure cannot be delayed > 6 hours, then vitamin K 10 mg IV plus 4-factor PCC (K-centra)
   3. Emergent reversal: Vitamin K 10 mg IV + 4-factor PCC is recommended for emergent reversal of warfarin therapy in adult patients with acute major bleeding or the need of warfarin reversal for an urgent surgery or invasive procedure
      1. Contraindications to PCC include disseminated intravascular coagulation (DIC) and known heparin-induced thrombocytopenia (HIT)
      2. Administer vitamin K concurrently to maintain vitamin K-dependent clotting factor concentrations once the effects of prothrombin complex concentrate have diminished
   4. 4-factor PCC dosing
      1. Dose is based upon patient’s INR and body weight
         1. INR 1.5 – 1.9: 25 units/kg (maximum 2500 units); this is a non-FDA approved dose and should be reserved for patients with life-threatening bleeding or emergent surgery
         2. INR 2 – 3.9: 25 units/kg (maximum 2500 units)

• INR 4 – 6: 35  units/kg (maximum 3500 units)

1. INR > 6: 50 units/kg (max 5000 units)

1. Each dose of PCC will be rounded to the nearest vial size
2. Repeat dosing is not recommended

5. 4-factor PCC administration
   1. Drug vials should be reconstituted with sterile water for injection and pooled into syringe(s) or an empty IV bag.
   2. Administration should take place within 4 hours of reconstitution
   3. Administer via a separate infusion line
   4. If medication has to be given IV push via a syringe, administration rate should not exceed 8.4 ml/min or 210 units/minute
6. Monitoring
   1. Onset of reversal is seen within 30 minutes of administration
   2. Recheck INR 15 – 30 minutes after 4-factor PCC administration and every 6 – 8 hours for the next 24 – 48 hours
   3. If INR remains elevated, consider FFP or another dose of Vitamin K

 

1. Reversal of Oral Factor Xa Inhibitors: Apixaban (Eliquis), Rivaroxaban (Xarelto), Edoxaban (Sayvasa)
   1. Normalization of hemostasis occurs within 12 – 24 hours of stopping rivaroxaban, apixaban, and edoxaban in patients with normal renal function
   2. There is no specific reversal agent for the factor Xa inhibitors
   3. Non-urgent reversal
      1. Hold anticoagulant
      2. If patient requires a surgery or invasive procedure, assess renal function and bleeding risk of procedure and hold medication per below table

Drug	Renal Function	Low Bleeding Risk Procedure	High Bleeding Risk Procedure
Apixaban	CrCl > 30	Hold 1 day (Skip 2 doses)	Hold 2 days (Skip 4 doses)
	CrCl = 15 – 29	Hold 1.5 days (Skip 3 doses)	Hold 3 days (Skip 6 doses)
	CrCl < 15	Hold 2 days (Skip 4 doses)	Hold 3 days (Skip 6 doses)
Edoxaban Rivaroxaban	CrCl > 30	Hold 1 day (Skip 1 dose)	Hold 2 days (Skip 2 doses)
	CrCl = 15 – 29	Hold 1.5 days (Skip 1 – 2  doses)	Hold 3 days (Skip 3 doses)
	CrCl < 15	Hold 2 days (Skip 2 doses)	Hold 3 days (Skip 3 doses)

4. Urgent reversal
   1. Hold anticoagulant
   2. Observe patient and provide supportive care per HASHTI principle
      1. Withholding the anticoagulant in patients with normal renal function may be enough to allow normalization of hemostasis
   3. Oral activated charcoal 50 grams PO/NG may be given if anticoagulant was ingested within 2 hours and patient has no contraindications to receiving charcoal
   4. If patient becomes hemodynamically unstable or requires surgery in less than 6 hours, then a 4-factor PCC may be considered
5. Emergent reversal
   1. Hold anticoagulant
   2. Oral activated charcoal 50 grams PO/NG may be given if anticoagulant was ingested within 2 hours and patient has no contraindications to receiving charcoal
   3. A 4-factor PCC may be considered for emergency surgery/procedures or in life‐threatening or uncontrolled bleeding,
   4. There is no data to support FFP administration for reversal of the anticoagulant effects of Factor Xa inhibitors
6. 4-factor PCC dosing and administration
   1. Optimal dosing is unknown, but 25 – 50 units/kg (maximum 5000 units) IV x 1 dose may be considered
   2. See 4-factor PCC administration listed above under warfarin reversal
7. Monitoring
   1. Consider checking a baseline PT/INR if suspect bleeding is due to over anticoagulation with a Factor Xa inhibitor
   2. An elevated PT/INR may suggest presence of a Factor Xa inhibitor if no other causes are present
   3. No need to repeat a PT/INR following administration of 4-factor PCC

 

1. Reversal of Oral Direct Thrombin Inhibitors: Dabigatran (Pradaxa)
   1. Normalization of hemostasis depends upon patient’s renal function
      1. Normal renal function: 12-24 h
      2. CrCl 50-80 mL/min: 24-36 h
      3. CrCl 30-50 mL/min: 36-48 h
      4. CrCl < 30 mL/min: > 48 h
   2. Non-urgent reversal
      1. Hold dabigatran
      2. If patient requires a surgery or invasive procedure, assess renal function and bleeding risk of procedure and hold medication per below table

Drug	Renal Function	Low Bleeding Risk Procedure	High Bleeding Risk Procedure
	CrCl > 80	Hold 1 day (Skip 2 doses)	Hold 2 days (Skip 4 doses)
Dabigatran	CrCl = 50 – 79	Hold 1.5 days (Skip 3 doses)	Hold 3 days (Skip 6 doses)
	CrCl = 30 – 49	Hold 2 days (Skip 4 doses)	Hold 4 days (Skip 8 doses)
	CrCl = 15 – 29	Hold 3 days (Skip 6 doses)	Hold 5 days (Skip 10 doses)
	CrCl < 15	No data; consider holding 4 days	No data; consider holding 6 days

3. Urgent reversal
   1. Hold dabigatran
   2. Observe patient and provide supportive care per HASHTI principle
      1. Withholding the anticoagulant in patients with normal renal function may be enough to allow normalization of hemostasis
   3. Oral activated charcoal 50 grams PO/NG may be given if anticoagulant was ingested within 2 hours and patient has no contraindications to receiving charcoal
   4. If patient becomes hemodynamically unstable or requires surgery in less than 8 hours, then reversal with idarucizumab (Praxbind) may be considered
4. Emergent reversal
   1. Hold dabigatran
   2. Oral activated charcoal 50 grams PO/NG may be given if anticoagulant was ingested within 2 hours and patient has no contraindications to receiving charcoal
   3. Idarucizumab (Praxbind) is FDA approved to reverse the anticoagulant effects of dabigatran for emergency surgery/ procedures or in life‐threatening or uncontrolled bleeding
   4. Hemodialysis is effective at removing approximately 60% of dabigatran in 2 hours
   5. There is no evidence to support FFP administration for reversal
5. Idarucizumab dosing and administration
   2. 5gm IV x 1; administer as 2 consecutive IV infusions of 2.5 g vials over 5 minutes each
   3. The second 2.5g vial must be administered within 15 minutes of the first vial
   4. Another 5 gram dose can be repeated if clinically relevant bleeding in combination with elevated coagulation parameters reappears or the patient requires a second emergency surgery or urgent procedure and has elevated coagulation parameters
6. Monitoring
   1. Onset of reversal effect is seen immediately after administration
   2. Repeat aPTT 4 hours and 12 – 24 hours after idarucizumab infusion
   3. Duration of reversal activity may last up to 72 hours

 

1. Reversal of Unfractionated Heparin (UFH)
   1. Non-urgent and Urgent reversal
      1. Hold heparin
      2. Due to the short half‐life of heparin, management of bleeding complications is primarily supportive and interruption of treatment will be sufficient to reverse the anticoagulant effect. The anticoagulant effect of intravenous heparin dissipates in 4 – 6 hours if the infusion is stopped.
   2. Emergent reversal
      1. Hold heparin
      2. Protamine sulfate may be used to reverse the anticoagulant effect of heparin
      3. There is an increased risk of hypersensitivity reaction, including anaphylaxis, in patients with a fish allergy or prior exposure to protamine
         1. Pre‐medicate with corticosteroids and antihistamines if at risk for protamine allergy
            1. Hydrocortisone 50‐100 mg IV x 1 over 15 minutes
            2. Diphenhydramine 50 mg IV/PO x1
         2. Protamine dose calculation
            1. 1 mg of protamine neutralizes approximately 100 units of UFH
            2. Use only the last 3 hours prior to reversal when considering the total amount of heparin administered to patient, due to the short half‐life of UFH. If the patient is on a continuous infusion, calculate the total amount administered over the past three hours prior to reversal.   If the patient is receiving SQ heparin, calculate the total amount administered within the past 3 hour prior to reversal only.

• Maximum single protamine dose is 50 mg and maximum dose in a 2 hour period is 100 mg

1. Multiple protamine doses may be required if bleeding or elevation of aPTT level persists

1. Protamine administration
   1. IV heparin reversal: Administer protamine IV with maximum infusion rate of 5 mg/min to prevent hypotension and bradycardia.
   2. SC heparin reversal: Administer bolus dose of protamine 25 mg and infuse remaining dose via intravenous infusion over 8 hours.
2. Monitoring
   1. Check an aPTT 5‐15 minutes after protamine infusion
   2. Onset of reversal effect is seen 5 minutes after administration

• Duration of reversal activity is approximately 2 hours

 

1. Reversal of Low‐Molecular Weight Heparin (LMWH): Enoxaparin (Lovenox)
   1. Non-urgent and Urgent reversal: Hold enoxaparin a minimum of 8 – 12 hours prior to procedure
   2. In emergent situations, protamine sulfate may be used as a partial reversal agent (neutralizes approximately 60% of LMWH’s anti-factor Xa activity)
      1. There is an increased risk of hypersensitivity reaction, including anaphylaxis, in patients with a fish allergy or prior exposure to protamine.
         1. Pre‐medicate with corticosteroids and antihistamines if at risk for protamine allergy.
            1. Hydrocortisone 50‐100 mg IV x 1 over 15 minutes
            2. Diphenhydramine 50 mg IV/PO x1
         2. Dose Calculation
            1. If last dose of LMWH was given in previous 8 hours, give 1 mg protamine for every 1 mg (or 100 units) of LMWH
            2. If the last dose of LMWH was given in the previous 8‐12 hours, give 0.5 mg protamine for every 1 mg (or 100 units) of LMWH

• If the last dose of LMWH was given more than 12 hours earlier, protamine is not recommended and an alternative agent may be needed to obtain hemostasis

1. Maximum dose of protamine is 50 mg and maximum dose in a 2 hour period is 100 mg

1. Administration
   1. Maximum protamine sulfate IV infusion rate is 5 mg/min to prevent hypotension and bradycardia
   2. Repeat dose 0.5 mg protamine for every 1 mg (or 100 units) of LMWH if bleeding continues or elevated anti‐factor Xa activity level after 2 – 4 hours
2. Monitoring
   1. Check a Hep Xa level 2 – 4 hours after protamine administration

 

1. Reversal of Subcutaneous Factor Xa Inhibitor: Fondaparinux (Arixtra)
   1. Non-urgent reversal
      1. Hold a therapeutic dose of fondaparinux 5 days before a procedure to ensure full clearance
   2. There is no specific reversal agent or pharmacologic antidote, but limited data suggests that 4-factor PCC (Kcentra) or Factor VIIa (NovoSeven) may be considered for emergency surgery or life‐threatening bleeding
      1. 4-factor PCC 25 – 50 units/kg (maximum 5000 units) IV x 1 dose
      2. Factor VIIa 90 mcg/kg IV x 1 dose

 

1. Intravenous Direct Thrombin Inhibitors: Argatroban, Bivalirudin (Angiomax)
   1. There is no specific reversal agent or pharmacologic antidote
   2. Due to the short half‐life of these agents (argatroban 40 – 50 minutes and bivalirudin 25 minutes) management of hemorrhagic complications is primarily supportive and interruption of treatment will be sufficient to reverse the anticoagulant effect

 

1. Anti-platelet agents: Aspirin, Clopidogrel (Plavix), Prasugrel (Effient), Ticagrelor (Brilinta), Ticlodipine (Ticlid)
   1. Discontinuation of antiplatelet agents due a bleeding event must be weighed against the patient’s risk of artrial thrombosis. The risk of thrombosis is high within 1 month of receiving a bare metal stent and within 3 months of receiving a drug eluting stent.
   2. Surgery should be delayed and therapy with the anti-platelet agent be continued for at least the minimum recommended duration for each stent type
   3. If surgery must be performed before these minimum time periods, it is best to consult with the treating cardiologist and surgeon. If the risk of major bleeding appears greater than the risk of stent thrombosis, antiplatelet therapy should be discontinued for as brief a period as possible.
      1. Aspirin should be continued if at all possible
      2. Clopidogrel and ticagrelor should be discontinued at least 5 days before surgery
      3. Prasugrel should be discontinued at least 7 days before surgery
      4. Ticlodipine should be discontinued at least 10 days before surgery
   4. Treatment of bleeding involves general hemostatic measures
   5. Platelet infusion may be considered for severe critical bleeds or in patients requiring neurosurgery, but it may increase the risk of arterial thrombosis

 

References:

1. Holbrook A. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.  2012 Feb;141(2 Suppl):e152S-84S
2. Frontera JA. Guidelines for reversal of antithrombotics in intracranial hemorrhage. Neurocritical Care 2016; 24: 6 – 46
3. Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI, for the Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14: 623–7.
4. Schulman S1, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients.  Journal of Thrombosis and  Haemostasis 2010; 8 (1): 202-4.
5. Dager W and Hellwig T. Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants.  American Journal of Health System Pharmacists 2016; 73: S14 – 26.
6. 2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation. Journal of the American College of Cardiology 2017; in press

 

Appendix A:  Pharmacokinetic parameters for select anticoagulants

DRUG CLASS	DRUG NAME	ELIMINATION HALF-LIFE		HD REMOVAL
Antiplatelet agents	Aspirin	15 – 30 minutes Anti-platelet effects persist for at least 4 days after stopping therapy		NO
	Clopidogrel (Plavix)	8 hours Anti-platelet effects last up to 10 days after stopping therapy		NO
	Prasugrel (Effient)	7 hours Anti-platelet effects last 5 – 7 days after stopping therapy		NO
	Ticagrelor (Brilinta)	7 hours Anti-platelet effects are decreased to 30% activity after 2.5 days		NO
	Ticlodipine (Ticlid)	24 – 36 hours Anti-platelet effects last 5 – 7 days after stopping therapy		NO
Direct thrombin inhibitor	Argatroban	40 – 50 minutes	~20%
	Bivalirudin (Angiomax)	25 minutes (up to 1 hour in severe renal impairment)	~25%
	Dabigatran (Pradaxa)	14 – 17 hours (up to 34 hours in severe renal impairment)	60%
Factor Xa inhibitor	Apixaban (Eliquis)	8-15 hours (longer in renal impairment)	NO
	Edoxaban (Savaysa)	10 – 14 hours (longer in renal impairment)	~25%
	Rivaroxaban (Xarelto)	Healthy: 5 – 9 hours Elderly: 11 – 13 hours (longer in renal impairment)	NO
	Fondaparinux (Arixtra)	17 – 21 hours (significantly longer in renal impairment)	NO
Heparin	Enoxaparin (Lovenox)	3 – 5 hours (longer in renal impairment)	~20%
	Heparin	30 – 90 minutes (dose dependent)	Partial
Vitamin K antagonist	Warfarin	20 – 60 hours	NO

 

 

Appendix B:  Reversal strategies for select agents

DRUG CLASS	DRUG NAME	STRATEGIES TO REVERSE OR MINIMIZE DRUG EFFECT
Antiplatelet agents	Aspirin Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) Ticlodipine (Ticlid)	·         Treatment involves general hemostatic measures ·         If neurosurgical intervention:  Platelet transfusion
Direct thrombin inhibitor	Argatroban Bivalirudin(Angiomax)	·         Turn off infusion
	Dabigatran (Pradaxa)	·         If ingested within 2 hours, administer activated charcoal 50 grams ·         Idarucizumab (Praxbind) 5gm IV x 1
Factor Xa inhibitor	Apixaban (Eliquis) Edoxaban (Savaysa) Rivaroxaban (Xarelto)	·         If ingested within 2 hours, administer activated charcoal 50 grams ·         Consider 4-factor PCC (KCentra) 25-50 units/kg (max 5000 units)
	Fondaparinux (Arixtra)	·         Consider 4-factor PCC 25 – 50 units/kg (max 5000 units) x 1 ·         Consider rFVIIa (Novoseven) 90 mcg/kg IV x 1
Heparin	Heparin	·         Use protamine for heparin neutralization Time since last dose of heparin Dose of protamine for each 100 units of heparin administered Immediate 1 mg 30 minutes – 2 hours 0.5 mg >2 hours 0.25 mg
Low Molecular Weight Heparin	Enoxaparin (Lovenox)	·         Use protamine for partial neutralization (~ 60%) Time since last dose of enoxaparin Dose of protamine for each 1mg of enoxaparin administered < 8 hours 1 mg 8-12 hours 0.5 mg >12 hours Unlikely to be useful
Vitamin K antagonist (Warfarin)	Condition Management INR = 4.5-10 and no bleeding ·         Hold warfarin ·         Resume warfarin at lower dose when therapeutic INR >10 and no bleeding ·         Hold warfarin ·         Give vitamin K 2.5 mg ORAL (for patients with mechanical valve, contact cardiologist before giving) ·         Resume warfarin at lower dose when therapeutic Any INR ·         Serious or life threatening bleed ·         Emergent surgery or invasive procedure required (< 6 hours) ·         Discontinue warfarin ·         Give vitamin 10 mg IV ·         Give 4-factor PCC (Kcentra) o    INR 1.5 – 3.9:  25 units/kg (max 2500 units) o    INR 4 – 6:  35  units/kg (max 3500 units) o    INR >6:  50 units/kg (max 5000 units) INR > 1.5 and urgent surgery or procedure (within  6 – 12 hours) ·         Hold warfarin ·         Type and cross, give FFP ·         Give Vitamin K 10 mg slow IV infusion (for patients with mechanical valve, contact cardiologist before giving vitamin K) o    Repeat INR in 8 hours o    If repeat INR > 1.5, give vitamin K 5 mg slow IV infusion ·         Resume warfarin 12 – 24 hours after surgery and when there is adequate hemostasis (contact physician) INR > 1.5 and surgery or procedure (within 48 hours) ·         Hold warfarin ·         Give vitamin K (for patients with mechanical valve, contact cardiologist before giving vitamin K) o    INR 1.5 – 4:  2.5 mg PO o    INR > 4:  5 mg PO o    Repeat INR in 12 hours o    If repeat INR > 1.5, vitamin K 2.5-5 mg PO ·         Resume warfarin 12 – 24 hours after surgery and when there is adequate hemostasis (contact physician)