U N C M E D I C A L C E N T E R G U I D E L I N E Emergent Anticoagulation Reversal - UNC … · R...

Developed by: Lindsey Splinter, PharmD, Kelly Dehne, PharmD, BCCCP, Kalynn Rohde, PharmD, BCCCP Reviewed by: Stephan Moll, MD, Raj, Kasthuri, MD, Abhi Mehrotra, MD, MBA, Rhonda Cadena, MD Approved by: Acute Care Services Pharmacy Practice Council, P&T Committee, MSEC

Last updated: October 2019 of 12

U N C M E D I C A L C E N T E R G U I D E L I N E

Emergent Anticoagulation Reversal

The purpose of this guideline is to provide guidance for the reversal of or management of bleeding while on treatment with anticoagulants. Recommendations provided in this document reflect current guidelines, clinical evidence and institutional initiatives. These recommendations are not intended to replace clinical judgement, but are intended to serve as a tool for decision-making.

T a b l e o f C o n t e n t s b y A n t i c o a g u l a n t :

Warfarin

Dabigatran

Edoxaban, Betrixaban, or Fondaparinux

Apixaban or Rivaroxaban

Unfractionated Heparin or Low Molecular Weight Heparin (Enoxaparin or Dalteparin)

Argatroban or Bivalirudin

Antiplatelet agents

I . B l e e d i n g D e f i n i t i o n s : S e e A p p e n d i x A

I I . E m e r g e n t R e v e r s a l o f O r a l A n t i c o a g u l a n t s

F I G U R E 1 . M A N A G E M E N T O F W A R F A R I N R E L A T E D B L E E D I N G E V E N T S

Patient currently taking warfarin

Non-major bleeding or routine/urgent procedure/surgery Major bleed or

emergent procedure/surgery

See warfarin dosing guidelines for management of supratherapeutic international normalized ratio (INR) without

bleeding

For minor bleeding or a routine/urgent procedure consider Vitamin K IV +/- 2 units of fresh frozen plasma (FFP)

Vitamin K 10 mg IV

AND

INR 1.50-3.99: KCentra® 25 units/kg x 1 dose

(Max dose: 2500 units)

INR 4.00-6.00: KCentra® 35 units/kg x 1 dose (Max dose: 3500 units)

INR > 6.00: KCentra® 50 units/kg x 1 dose

(Max dose: 5000 units)

Recheck INR 10-30 minutes after KCentra® administration and every 6 hours for 24 hours.

Recheck INR in 6-12 hours

https://unchcs.intranet.unchealthcare.org/dept/Pharmacy/mc/Clinical%20Guidelines/warfarinadultdosing.pdf



O r d e r i n g a n d A d m i n i s t r a t i o n

A. Vitamin K

1. Subcutaneous or intramuscular doses are not recommended as routine care. Subcutaneous administration

leads to erratic absorption and intramuscular administration may lead to the development of hematomas in the

setting of therapeutic anticoagulation.

2. Full effect of vitamin K on warfarin reversal occurs approximately 24 hours after administration. Partial effects

may be seen 6-12 hours after administration.

3. Doses of vitamin K greater than 10 mg are excessive and do not reverse anticoagulation more quickly.

B. 4-Factor Prothrombin Complex Concentration (KCentra®)

1. Ordering:

i. KCentra® doses are calculated as units/kg using total body weight, with the maximum dosing weight

of 100 kg.

ii. During verification, the Sterile Products Area pharmacist will verify and prepare dose rounded to

nearest vial size within 10% of originally ordered dose.

2. Administration:

i. Administer via infusion pump at a rate of 3 units/kg/minute; do not exceed a rate of 8.4 mL/minute

(504 mL/hour).

ii. After KCentra® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing

at the same rate as KCentra® dose to ensure administration of full dose.



F I G U R E 2 . M A N A G E M E N T O F D A B I G A T R A N R E L A T E D B L E E D I N G E V E N T S


A. Idarucizumab (Praxbind®)

1. Administration:

i. Praxbind® is stored in the refrigerator.

ii. Administer promptly once vials have been removed from box (stability after light exposure is 6 hours).

iii. Administer both vials undiluted as an IV bolus (2.5 g in each vial) over 5 minutes via an infusion pump

(pump entry defaults to 600 mL/hour).

iv. The second vial should be administered no later than 15 minutes after the end of the first vial.

v. After Praxbind® dose is complete; administer a 50 mL bag of normal saline using the same IV tubing

at the same rate as Praxbind® dose to ensure administration of full dose.

Patient currently taking dabigatran*

Non-major bleeding or routine/urgent procedure/surgery

Major bleeding or emergent procedure/surgery

Delay next dose or discontinue dabigatran

1) Administer idarucizumab (Praxbind®) 5 g (2 vials) IV x 1 dose 2) For persistent refractory bleeding (> 1 hour), consider a hematology consult

3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin

time (TT), complete blood count (CBC)

In the setting of acute renal failure, hemodialysis may be considered to assist with drug removal

*If presenting within 2 hours of ingestion of dabigatran dose, consider administering activated charcoal 50 g by mouth x 1 dose -Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding



F I G U R E 3 . M A N A G E M E N T O F E D O X A B A N , B E T R I X A B A N , O R F O N D A P A R I N U X

R E L A T E D B L E E D I N G E V E N T S


A. 4-Factor Prothrombin Complex Concentration (KCentra®)

1. Ordering:


of 100 kg.



2. Administration:


(504 mL/hour).

ii. After KCentra® dose is complete; administer a 50 mL bag of normal saline using the same IV tubing


Patient currently taking edoxaban*, betrixaban*, or fondaparinux



Delay next dose or discontinue factor Xa inhibitor

1) Administer KCentra® 50 units/kg IV x 1 dose (Max dose: 5000 units)

2) For persistent refractory bleeding (> 1 hour), consider a hematology consult

3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time (PT),

activated partial thromboplastin time (aPTT), complete blood count (CBC)

*If presenting within 2 hours of ingestion of edoxaban or betrixaban dose, consider administering activated charcoal 50 g by mouth x 1 dose

-Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding



F I G U R E 4 . M A N A G E M E N T O F A P I X A B A N O R R I V A R O X A B A N R E L A T E D B L E E D I N G

E V E N T S



1. Ordering:


of 100 kg.



2. Administration:


(504 mL/hour).



B. Coagulation factor Xa (recombinant), inactivated-zhzo (Andexxa®)

1. Ordering:

i. Andexxa® is restricted to use for intracranial hemorrhage only and must be ordered or

approved by a Neurocritical Care Attending

ii. Select low or high dose based on anticoagulant dose and timing of last dose (see Table 1)

2. Administration:

Patient currently taking apixaban* or rivaroxaban*



Delay next dose or discontinue factor Xa inhibitor 1) Andexxa® with Neurocritical Care

Attending approval only 2) See Table 1 for dosing

recommendations

*If presenting within 2 hours of ingestion of apixaban or rivaroxaban dose, consider administering activated charcoal 50 g by mouth x 1 dose

-Avoid activated charcoal in patients who may require a gastrointestinal procedure for suspected or confirmed bleeding

1) Administer KCentra® 50 units/kg IV x 1 (Max dose: 5000 units)

2) For persistent refractory bleeding (> 1 hour), consider a hematology consult

3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time

(PT), activated partial thromboplastin time (aPTT), complete blood count

(CBC)

Intracranial hemorrhage ONLY All other bleeding or emergent procedure/surgery



i. Administer bolus and infusion using a 0.2 or 0.22 micron in-line filter (supplied by Central

Pharmacy). The same tubing and filter should be used for the bolus and infusion.

ii. The infusion should begin within 2 minutes of completion of the bolus dose.

iii. After Andexxa® dose is complete, administer a 50 mL bag of normal saline using the same IV tubing

and filter at the same rate as Andexxa® dose to ensure administration of full dose.

Table 1. Andexxa® Dosing By Anticoagulant and Time of Last Dose

Anticoagulant Anticoagulant Last Dose Administered (mg taken)

Timing of Anticoagulant Last Dose

< 8 hours or unknown 8 hours-18 hours

Apixaban < 5 mg Low dose

Low dose > 5 mg or unknown mg dose High dose

Rivaroxaban < 10 mg Low dose

> 10 mg or unknown mg dose High dose

1. Low dose: 400 mg IV bolus (30 mg/min (180 mL/hour)) followed by 480 mg (4 mg/min (24 mL/hour)) over 2 hours

2. High dose: 800 mg IV bolus (30 mg/min (180 mL/hour)) followed by 960 mg (8 mg/min (48 mL/hour)) over 2 hours



I I I . E m e r g e n t R e v e r s a l o f I n t r a v e n o u s a n d S u b c u t a n e o u s A n t i c o a g u l a n t s

F I G U R E 5 . M A N A G E M E N T O F U N F R A C T I O N A T E D H E P A R I N ( U F H ) O R L O W -

M O L E C U L A R W E I G H T H E P A R I N ( L M W H ) R E L A T E D B L E E D I N G E V E N T S


A. Protamine Sulfate

1. Administration:

i. Administer protamine sulfate as a slow IV push with maximum rate of 5 mg/minute to prevent

hypotension and bradycardia

ii. Patients with history of fish allergies or prior exposure to protamine should receive pre-medications

with hydrocortisone and diphenhydramine.

Patient currently taking UFH or LMWH



Delay next dose or discontinue heparin infusion or low molecular weight heparin

injections

Unfractionated Heparin (IV) 1) Administer protamine sulfate*: Max dose: 50 mg

a. Calculate the units of heparin administer within the last 3 hours b. Administer 1 mg of protamine for every 100 units of heparin administered in last

3 hours

Unfractionated Heparin (subcut) 1) Administer protamine sulfate*: Max dose: 50 mg

a. Calculate the units of heparin administer within the last 3 hours b. Administer 1 mg of protamine for every 100 units of heparin administered in last

3 hours c. Monitor activated partial thromboplastin time (aPTT) every 3 hours and

consider repeat protamine (0.5 mg per 100 units of heparin administered) if bleeding continues

Low Molecular Weight Heparin: 1) Administer protamine sulfate*: Max dose: 50 mg

a. Enoxaparin: Determine timing of last dose

i. If dose within the last 8 hours, give 1 mg of protamine for every 1 mg of enoxaparin administered

ii. If dose within the last 8-12 hours, give 0.5 mg of protamine for every 1 mg of enoxaparin administered

iii. If dose more than 12 hours ago, protamine sulfate is not recommended. Consider checking LMWH anti-factor Xa level in the setting of renal failure. Administer 0.5 mg of protamine for every 1 mg of enoxaparin administered if level elevated.

b. Dalteparin: Determine timing of last dose

i. If dose within last 8 hours, give 1 mg of protamine for every 100 units of dalteparin administered

*Patients with fish allergies or prior exposure to protamine are at increased risk for hypersensitivity reactions, including anaphylaxis, pre-medicate with the following:

Hydrocortisone 50 mg IV x 1 dose

Diphenhydramine 50 mg IV or by mouth x 1 dose



F I G U R E 6 . M A N A G E M E N T O F D I R E C T T H R O M B I N I N H I B I T O R R E L A T E D

B L E E D I N G E V E N T S



1. Ordering:


of 100 kg.



2. Administration:


(504 mL/hour).



Patient currently taking argatroban or bivalirudin



Discontinue direct thrombin inhibitor continuous infusion

1) Administer KCentra® 50 units/kg IV x 1 (max dose: 5000 units)

2) For persistent refractory bleeding, consider a hematology consult

3) To investigate potential causes of bleeding obtain the following: serum creatinine (SCr), prothrombin time (PT),

activated partial thromboplastin time (aPTT), thrombin time (TT), complete blood count (CBC)



I I I . M a n a g e m e n t o f A n t i p l a t e l e t A g e n t R e l a t e d B l e e d i n g E v e n t s

Duration of platelet inhibition by antiplatelet agents that irreversibly inhibit platelet function is not dependent on the agent half-life, but rather may persist for 5-7 days. Utilize Table 2 below as a guide for interpreting the peak and duration of action of these agents.

Table 2. Antiplatelet PK/PD profiles

Agent Time to Maximum

Antiplatelet Effect

Elimination Half-Life

Platelet Inhibition

Notes

Aspirin 30 minutes 15-30 minutes Irreversible Antiplatelet effects begin within one hour of

dose and persist for at least 4 days after stopping therapy.

Clopidogrel (Plavix®)

3-7 days 8 hours Irreversible

More rapid inhibition of platelet function is achieved with loading doses; antiplatelet effect

persists for up to 10 days after stopping therapy.

Prasugrel (Effient®)

30 minutes 7 hours Irreversible Antiplatelet effect persists for 5-7 days after

stopping therapy.

Ticagrelor Brilinta®)

1.5 hours 7 hours Reversible Antiplatelet effects are decreased to 30% activity after stopping therapy for 2.5 days.

Ticlopidine (Ticlid®)

1-3 hours 24-36 hours Reversible Antiplatelet effect persists for 5-7 days after

stopping therapy.

Cangrelor (Kengreal®)

Seconds with IV administration

2-5 minutes Reversible Normal platelet function returns by 60 minutes

after infusion is stopped.

Table adapted from Ortel TL. Blood. 2012;120(24):4699-4705.

1. Management strategies for antiplatelet associated bleeding events:

a. There are no specific reversal agents for antiplatelet agents, therefore treatment of bleeding involves

general hemostatic measures.

b. Discontinuation of antiplatelet agents due to bleeding must be weighed against the patient’s risk of

arterial thrombosis. The risk of thrombosis is particularly high within 1 month of receiving a bare metal

coronary stent and within 3 months of receiving a drug eluting coronary stent. Premature cessation of

dual anti-platelet therapy in these situations can lead to stent thrombosis, which can potentially be

fatal.

c. Antiplatelet agents should be reinstated as soon as hemostasis is obtained

d. Platelet infusion may be considered as additional measure for severe critical bleeds, or prevention

of bleeds before emergency surgery, but it may confer a risk of arterial thrombosis.

e. Tranexamic acid (Lysteda®) or Aminocaproic acid (Amicar®) can be considered

i. Tranexamic acid: 10 mg/kg IV bolus administered over 10 minutes (maximum bolus dose:

1000 mg IV once)

ii. Aminocaproic acid: 50 mg/kg IV bolus administered over 60 minutes (maximum bolus dose:

5000 mg IV once)

iii. Continuation of tranexamic acid or aminocaproic acid after the bolus can be considered for

continued bleeding

f. DDAVP is likely not a safe option, as it can lead to arterial vasospasm.

g. Hematology/Coagulation Consult Service may be consulted if a risk versus benefit evaluation is

required.



R e f e r e n c e s :

1. Antithrombotic therapy and prevention of thrombosis 9th ed: American College of Chest Physicians

evidence-based clinical practice guidelines. CHEST. 2012;141 (2_suppl).

2. Bijsterveld NR et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the

pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106:2550-2554.

3. Burnette AE et al. Guidance for the practical management of the direct oral anticoagulants (DOACs)

in VTE treatment. J Thromb Thrombolysis. 2016;41:206–232

4. Dager WE et al. Reversal of elevated INR and bleeding with low-dose recombinant activated factor

VII in patients receiving warfarin. Pharmacotherapy. 2006;26(8):1091-8.

5. Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate.

Circulation. 2011;124: 1573-1579.

6. Holland L et al. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD)

in correcting supratherapeutic INR due to warfarin overdose. Transfusion. 2009; 49(6):1171-1177

7. Levi M et al. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med

2010; 363:1791-800.

8. Makris M et al Guideline on the management of bleeding in patients on antithrombotic agents. British

Journal of Hematology. 2012;160(1):35-46.

9. Nishijima DK et al. The efficacy of factor VIIa in emergency department patients with warfarin use and

traumatic intracranial hemorrhage. Acad Emerg Med. 2010;17(3):244-51.

10. Ortel TL. Perioperative management of patients on chronic antithrombotic therapy. Blood. 2012 Dec

6;120(24):4699-705.

11. Pollack CV, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, et al. Idarucizumab for

Dabigatran Reversal. N Engl J Med. 2015;373(6):511-20.

12. Van Ryn J et al. Dabigatran etexilate-a novel, reversible, oral direct thrombin inhibitor: interpretation

of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010;103(6):1116-

1127

13. UNCH Blood Derivative Compendium v02012 06 21.

14. Vavra KA et a. Recombinant factor VIIa to manage major bleeding from newer parenteral

anticoagulants. Ann Pharmacother. 2010;44:718-26.

15. www. Clotconnect.org

16. Product Information: PRAXBIND intravenous injection, idarucizumab intravenous injection.

Boehringer Ingelheim Pharmaceuticals (per FDA), Ridgefield, CT, 2015.

17. Witt D et al. Guidance for the practical management of warfarin therapy in the treatment of venous

thromboembolism. J Thromb Thrombolysis 2016;41:187–205.

18. Siegal DM, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med 2015 Dec

17;373(25):2413-24

19. Connolly SJ, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N

Eng J Med 2016 Sep 22;375(12):1131-41

20. Kaatz S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding in

studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical

patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119-2126.

21. Cuker, et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J

Hematol 2019;94(6):697-709.

22. Cushman M, et al. 2011 Clinical practice guide on anticoagulant dosing and management of

anticoagulant-associated bleeding complications in adults. American Society of Hematology Clinical

Pocket Guide. 2011.

23. Shi J, Ji H, Ren F, et al. Protective effects of tranexamic acid on clopidogrel before coronary artery

bypass grafting: a multicenter randomized trial. JAMA Surg. 2013;148(6):538:547.



24. Weber CF, Gorlinger K, Byhahn C, et al. Tranexamic acid partially improves platelet function in

patients treated with dual antiplatelet therapy. Eur J Anaesthesiol. 2011;28(1):57-62.

A p p e n d i x A : B l e e d i n g D e f i n i t i o n s

M a j o r B l e e d i n g :

Symptomatic bleeding into a critical site: o Intracranial o Intraspinal o Intraocular o Retroperitoneal o Intraarticular o Pericardial o Intramuscular with compartment syndrome

Bleeding leading to ≥ 2 g/dL hemoglobin decrease

Bleeding leading to transfusion of ≥ 2 units of packed red blood cells

Activation of the massive transfusion protocol

Bleeding leading to hypotension requiring vasopressors

M i n o r B l e e d :

Bleeding leading to < 2 g/dL hemoglobin decrease

Bleeding leading to transfusion of < 2 units of packed red blood cells

Gross hematuria not associated with trauma

Epistaxis and oral bleeding that is prolonged and unresponsive to topical therapies

Bruising, bleeding gums, oozing from injection sites

Bleeding at a compressible site



A p p e n d i x B : A n t i c o a g u l a n t P h a r m a c o k i n e t i c C o n s i d e r a t i o n s

Drug Elimination Half-Life Mechanism of

Clearance Removed by

Dialysis In-House Laboratory Values for

Detecting Drug Presence

Apixaban (Eliquis®)

12 hours

(prolonged in renal impairment) Renal/Hepatic No

Prothrombin time (PT) (prolonged or normal)

LMWH anti-factor Xa level (elevated)

Argatroban 40-50 minutes

(prolonged in hepatic dysfunction)

Hepatic 20% Activated partial thromboplastin time

(aPTT) (prolonged)

Betrixaban (Bevyxxa®)

19 to 27 hours Renal/Hepatic No Prothrombin Time (PT) (prolonged or normal)

Bivalirudin (Angiomax®)

25 minutes (up to 1 hr in severe renal

impairment) Renal 25%

Prothrombin time (PT) (prolonged)

Thrombin time (TT) (prolonged)

Activated partial thromboplastin time (aPTT)

(prolonged)

Dabigatran (Pradaxa®)

14 hours (up to 34 hrs in severe renal

impairment) Renal 62-68%



(prolonged or normal)

Edoxaban (Savaysa®)

10 to 14 hours (prolonged in renal

impairment) Renal/Hepatic No


Enoxaparin (Lovenox®)

3-5 hours (prolonged in renal

impairment) Renal 20%

LMWH anti-factor-Xa (elevated)

Prothrombin time (PT) (prolonged)


Fondaparinux (Arixtra®)

17-21 hours (significantly prolonged in

renal impairment) Renal No


Activated partial thromboplastin time

(aPTT) (prolonged or normal)

Heparin 30-90 minutes Hepatic Partial


(prolonged)

UFH anti-factor Xa level (elevated)

Rivaroxaban (Xarelto®)

Healthy: 5-9 hours Elderly: 11-13 hours (prolonged in renal

impairment)

Renal/Hepatic No


LMWH anti-factor Xa level (elevated)

Warfarin 20-60 hours Hepatic No Prothrombin time (PT)

(prolonged)

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