Mark Crowther, MD, MSc, FRCPC, FRSC, and Truman J. Milling Jr., MD, FACEP, prepared useful Practice Aids pertaining to DOAC reversal agents for this CME/MOC activity titled “Managing Bleeding Events in Patients Receiving Direct Oral Anticoagulants: When Is It Appropriate to Implement Reversal Strategies in Patients With GI Bleeding?” For the full presentation, monograph, complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/2FK3x3S. CME/MOC credit will be available until January 25, 2022.

1. Guidance on DOAC Reversal Agents1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
Question Guidance Statement
When should reversal agents be used to
manage DOAC-associated bleeding?
• Treat all patients with DOAC-associated bleeding with supportive measures; a
reversal agent is only recommended if the bleeding is life-threatening, into a critical
organ, or not controlled with maximal supportive measures and there is demonstration
or reasonable expectation that the patient has clinically relevant plasma DOAC levels
How should reversal agents be used to
manage dabigatran-associated bleeding?
• If warranted, treat with idarucizumab 5 g IV; if idarucizumab is not available, treat with
APCC 50 units/kg IV
How should reversal agents be used to manage
factor Xa inhibitor-associated bleeding?
• For rivaroxaban- or apixaban-associated major bleeding, if warranted, treat with
andexanet alfa dosed according to prescribing information; if andexanet alfa is not
available, treat with four-factor PCC 2,000 units
• For edoxaban- or betrixaban-associated major bleeding, if warranted, off-label
treatment with either a high dose of andexanet alfa (800 mg bolus given at 30 mg/min
followed by continuous infusion of 8 mg/min for up to 120 min) or four-factor PCC
2,000 units
When should reversal agents be used
before an invasive procedure?
• Only administer a reversal agenta
if the procedure cannot be safely performed while
the patient is anticoagulated, cannot be delayed, and there is demonstration or
reasonable expectation that the patient has clinically relevant plasma DOAC levels
How should reversal agents be used to
manage a patient treated with dabigatran who
has major or life-threatening bleeding
before an invasive procedure?
• Treat with idarucizumab 5 mg IV; if idarucizumab is not available, treat with APCC
50 units/kg IV

2. Guidance on DOAC Reversal Agents1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
a
There is no evidence for andexanet alfa for perioperative use, unlike idarucizumab.
1. Cuker A et al. Am J Hematol. 2019;94:697-709.
Question Guidance Statement
Are reversal agents indicated
for patients who present with a DOAC
overdose without bleeding?
• Reversal agents are not recommended for patients who present with DOAC overdose
and no bleeding
Are reversal agents indicated
for patients treated with DOACs who
present with trauma but no bleeding?
• The routine use of reversal agents in DOAC-treated patients who present with trauma
without bleeding is not recommended
What strategies can be employed by
healthcare systems to promote the optimal
utilization of DOAC reversal agents?
• Promote multidisciplinary, shared stewardship of DOAC reversal agents that should be
developed and implemented; additionally, the utilization of evidence-based clinical tools
and processes that facilitate adherence with agreed-upon restrictions for judicious
prescribing and use
• Streamline to the fullest extent possible via leveraging of EHRs, as well as maximized
efficiency of pharmacy order processing, admixture, and delivery strategies
• Develop contingency plans to be prepared for a variety of acquisition challenges and
close collaboration with vendors and billing departments to capitalize on cost mitigation
opportunities
• Conduct periodic formal evaluations of DOAC reversal practices to assess for
appropriateness and identify opportunities for further optimization
• Establish dedicated stewardship programs, whenever possible, to drive development,
implementation, consistent application, and evaluation of anticoagulation-related
optimization strategies including, but not limited to, appropriate and judicious use
of DOAC reversal agents

3. DOAC Reversal Agents
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
Xa Inhibitors
• Rivaroxaban
• Apixaban
• Edoxaban
Direct thrombin
inhibitor
• Dabigatran
Reversal
agent:
Idarucizumab
Reversal
agent:
Andexanet alfa
VKA
• Warfarin
I
Prothrombin
Intrinsic system
(surface contact)
VIIIa
XII XIIa
IX
XIa
VIII
IXa
X
Va
V
II
VIIa
IIa
Tissue factor
Extrinsic system
(tissue damage)
Fibrin
VII
Clot
VKA
• Warfarin
VKA
• Warfarin
VKA
• Warfarin
Reversal
agents:
PCC and
Vitamin K
Reversal
agents:
PCC and
Vitamin K
Reversal
agents:
PCC and
Vitamin K
Reversal
agents:
PCC and
Vitamin K
Mode of Action of Anticoagulants1,2
Ia
Fibrinogen
Thrombin
XI
Xa

4. DOAC Reversal Agents
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
Andexanet Alfa Idarucizumab 4F-PCC APCC
Trade name Andexxa Praxbind Kcentra FEIBA
Administration IV and infusion IV Infusion IV or infusion
Recommended
dosage
Low dose
• Initial IV bolus: 400 mg
at target rate of 30 mg/min
• Follow-on IV infusion:
4 mg/min for up to 120 min
High dose
• Initial IV bolus: 800 mg
at a target rate of 30 mg/min
• Follow-on IV infusion:
8 mg/min for up to 120 min
5 g 2,000 units4
• Control and prevention
of bleeding: 50-100 unit/kg
• Perioperative management:
50-100 units/kg
• Routine prophylaxis: 85 units/kg
Half-life
• PD: 30-60 min
• Terminal: 5-7 h
• PD: 45 min
• Terminal: 4-8 h
• Dependent on half-lives
of individual clotting
factors
• Elevated levels of
clotting factors likely
persist for at least 24 h
• Dependent on half-lives
of individual clotting factors
• Elevated levels of clotting
factors likely persist for at
least 24 h
Onset
of action
2-5 min <5 min
Nonspecific
prohemostatic agent
Nonspecific
prohemostatic agent
Characteristics of DOAC Reversal Agents3

5. DOAC Reversal Agents
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
1. https://ashpadvantagemedia.com/doacresources/files/doacresources-discussion-guide.pdf. 2. Baugh C et al. Ann Emerg Med. 2020;76:470-485. 3. http://www.accessdata.fda.gov. 4. Cuker A et al. Am J Hematol. 2019;94:697-709.
FXa Inhibitor FXa Inhibitor Last Dose <8 h or Unknown 8 h
Rivaroxaban
10 mg Low dose Low dose
>10 mg or unknown High dose Low dose
Apixaban
5 mg Low dose Low dose
>5 mg or unknown High dose Low dose
Dosing Recommendations3
Andexanet Alfa
APCC
Dose, unit/kg Dosing Frequency, h Duration
Control and prevention of bleeding
Joint hemorrhage 50-100 12 Until pain and acute disabilities improve
Mucous membrane bleeding 50-100 6 At least 1 day or until bleeding resolved
Soft tissue hemorrhage (eg, retroperitoneal
bleeding)
100 12 Until resolution of bleed
Other severe hemorrhage (eg, CNS bleeds) 100 6-12 Until resolution of bleed
Perioperative management
Preoperative 50-100 One-time dose Immediately before surgery
Postoperative 50-100 6-12
Until resolution of bleed
and healing achieved
Routine prophylaxis
85 Every other day

6. Considerations for Restarting Anticoagulation1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
Suggest
discontinuing
anticoagulant
Suggest delaying restart
of anticoagulant
Suggest restarting
anticoagulant
Does ≥1 of the following clinical indications apply?
• NVAF with CHA2DS2-VASc score <2 in men and <3 in women
• Temporary indication for OAC (eg, postsurgical prophylaxis, OAC after an anterior MI without left ventricular
thrombus, post-LAA closure device placement)
• Recovered acute stress cardiomyopathy (eg, Takotsubo cardiomyopathy)
• First-time provoked VTE >3 months ago
• Bioprosthetic valve placement in the absence of AF >3 months ago
Yes
Yes
Does ≥1 of the following clinical indications apply?
• Bleeding occurred at a critical site
• Patient is at high risk of rebleeding or of death/disability with rebleeding
• Source of bleeding has not yet been identified
• Surgical/invasive procedure planned
• After informed discussion, patient declines or does not wish
to restart anticoagulant at this time
No
No

7. Considerations for Restarting Anticoagulation1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHP40
1. Tomaselli GF et al. J Am Coll Cardiol. 2020;76:594-622.
Does the patient fall into one
of the following groups?
• NPO
• Awaiting an invasive
procedure
• Pregnancy
• High risk of bleeding
• Being bridged back to VKA
with high thrombotic risk
Yes
No
Suggest therapy be continued
with parenteral anticoagulation
Choose an OAC: Consider switching OAC
if reversible cause related to the OAC contributed
to the bleed (eg, high INR, renal function variation)
Reassess the severity
of bleeding
Exit
pathway
• Reassess need for aspirin in stable CAD
• Reassess need for DAPT in patients after PCI
and/or ACS and consider discontinuing aspirin
Suggest restarting anticoagulant
Is patient on concomitant
antiplatelet therapy?
Yes
No
Is the patient taking concurrent medications
that interact with OAC levels (eg, antiretrovirals,
antifungals, antibiotics, antiarrhythmics)?
Suggest pharmacy consultation and consideration
of switching either OAC or interacting medication
Did bleeding reoccur?
Yes No
Yes No