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Antithrombotic Reversal - Adult - Inpatient

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1
Antithrombotic Reversal – Adult –
Inpatient
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ................................................................................................................................... 4
METHODOLOGY .................................................................................................................... 4
DEFINITIONS.......................................................................................................................... 5
INTRODUCTION ..................................................................................................................... 5
RECOMMENDATIONS ............................................................................................................ 5
UW HEALTH IMPLEMENTATION ........................................................................................... 15
APPENDIX A. EVIDENCE GRADING SCHEME(S) ...................................................................... 16
REFERENCES ........................................................................................................................ 21
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2


Contact for Content:
Name: Anne Rose, PharmD – Pharmacy Department
Phone Number: (608) 263-9738
Email Address: ARose@uwhealth.org

CPG Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS, Director of Drug Policy
Phone Number: (608) 265-0341
Email Address: PTrapskin@uwhealth.org

Guideline Author(s):
Anne Rose, PharmD – Anticoagulation Stewardship Program

Coordinating Team Members:
John Hoch, MD – Department of Surgery – Vascular
Kraig Kumfer, MD, PhD – Hospital Medicine
Joshua Medow, MD – Neurological Surgery
John Sheehan, MD – Hematology
Eliot Williams, MD - Hematology

Review Individuals/Bodies:
Donna Lawler – Special Anticoag Lab

Committee Approvals/Dates:
Inpatient Anticoagulation Committee (Last Periodic Review: 09/11/17)

Pharmacy & Therapeutics Committee (Last Periodic Review: 11/2017)

Release Date: October 2017 | Next Review Date: October 2019
Original Release 2013



















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3


Executive Summary
Guideline Overview
The intent of this guideline is to provide evidence-based recommendations for the treatment of
bleeding in patients on antithrombotic therapy and standardize care within UW Health. The
guideline provides reversal recommendations for the following: warfarin, oral and intravenous
direct thrombin inhibitors, oral anti-Xa inhibitors, heparin-based medications, fondaparinux,
NSAIDs, P2Y12 ASP receptor inhibitors, phosphodiesterase inhibitors and glycoprotein IIb/IIIa
inhibitors. Procoagulant agent use includes desmopressin, plasma (commonly referred to as
FFP), factor 7A, idarucizumab, prothrombin complex concentrate (PCC), phytonadione, and
protamine.

Key Revisions (2017 Periodic Review)
List any MAJOR revisions which were made between full periodic reviews or during last review.
1. Addition of low, fixed dose prothrombin complex concentrate for warfarin reversal
2. Addition of reversal recommendations for antiplatelet agents

Key Practice Recommendations
To quickly view reversal recommendations for specific antithrombotic medications select
hyperlink below.

1. Warfarin and Prothrombin Complex Concentrate (PCC)
2. Dabigatran
3. Anti-Xa: Apixaban, Rivaroxaban, Edoxaban
4. Heparin and Low Molecular Weight Heparin
5. Direct Thrombin Inhibitors: Argatroban and Bivalirudin
6. Fondaparinux
7. Aspirin
8. Non-steroidal Anti-inflammatory Drugs (NSAIDs)
9. P2Y12 ADP Receptor Inhibitors (clopidogrel, prasugrel, ticagrelor)
10. Phosphodiesterase Inhibitor (cilostazol)
11. Glycoprotein IIb/IIIa inhibitor (eptifibatide, abciximab)

Companion Documents
1. Appendix A GRADE Methodology Evidence Grading Scheme
2. Appendix B Treatment of Bleeding Associated with Oral Anticoagulants
3. Appendix C Treatment of Bleeding Associated with Parenteral Anticoagulants
4. Appendix D Treatment of Life Threatening Bleeding Associated with Anticoagulants
5. Appendix E Administration Rate of Intravenous Procoagulant Agents
6. Appendix F Literature Summary for Low Fixed Dose PCC
7. UW Health Warfarin Management - Adult - Ambulatory - Clinical Practice Guideline
8. UW Health Warfarin Management - Adult - Inpatient Clinical Practice Guideline
9. UW Health Heparin- Induced Thrombocytopenia – Adult – Inpatient Clinical Practice
Guideline
10. UW Health Unfractionated Heparin (Therapeutic Dosing) - Adult - Inpatient Clinical Practice
Guideline
11. UW Health Antithrombotics in Non-Valvular Atrial Fibrillation - Adult - Inpatient/Ambulatory
Clinical Practice Guideline
12. UW Health Indications for Blood Product Transfusion – Adult – Inpatient/Ambulatory Clinical
Practice Guideline
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13. UW Health IV Administration Guideline – Adult – Inpatient/Ambulatory Clinical Practice
Guideline

Scope
Disease/Condition(s): Treatment of adult non-hemophiliac bleeding or with high potential for
bleeding (i.e. intra-operatively) due to antithrombotic therapy at UW Health.

Clinical Specialty: Neurology, Trauma, Critical Care, Cardiology, Surgery, Emergency,
Nursing, Pharmacy

Intended Users: Physicians, mid-level providers, pharmacists, nurses, students

Objective(s): Provide evidence-based recommendations for the treatment of bleeding in
patients on antithrombotic therapy and standardize care within UW Health.

Target Population: Adult inpatient and emergency department patients

Interventions and Practices Considered: Procoagulant agent use includes desmopressin,
plasma (commonly referred to as FFP), factor 7A, idarucizumab, prothrombin complex
concentrate (PCC), phytonadione, and protamine.

Major Outcomes Considered: Control of bleeding, improved neurological, cardiac, and renal
outcomes. Thromboembolic events post reversal.

Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches (e.g., PUBMED) were conducted by the guideline author(s) and
workgroup members to collect evidence for review. Expert opinion and clinical experience were
also considered during discussions of the evidence.

Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external
organizations and/or arrived at a consensus through discussion of the literature and expert
experience. All recommendations endorsed or developed by the guideline workgroup were
reviewed and approved by other stakeholders or committees (as appropriate).

Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Recommendations developed by external organizations maintained the evidence grade
assigned within the original source document and were adopted for use at UW Health.

Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup using an algorithm
adapted from the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology (see Figure 1 in Appendix A).

Rating Scheme for the Strength of the Evidence/Recommendations:
See Appendix A for the rating scheme(s) used within this document.

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Definitions
1

1. Minor bleed – epistaxis lasting less than 1 hour, small amount of blood in stool, urine or oral
cavity.
2. Non- major bleeding – bleeding with decline in Hgb of <2 g/dL or requiring ≤ 1 unit of blood
or packed cells.
3. Major bleed - Acute major bleeding that includes one of the following: potentially life-
threatening, acute Hgb decline of ≥ 2 g/dL or acute bleeding requiring at least two units of
blood or packed cells (International Society on Thrombosis and Haemostasis).
4. Life-threatening bleed – fatal bleeding, symptomatic intracranial bleeding, reduction in
hemoglobin of at least 5 g/dL, transfusion of at least 4 units of blood or packed cells,
bleeding associated with hypotension requiring use of intravenous inotropic agents, bleeding
necessitating surgical intervention (International Society on Thrombosis and Haemostasis).
5. Massive trauma bleeding – loss of complete blood volume (approximately 0.7 L/kg lean
body weight) within 24 hours or half of blood volume within three hours.
Introduction
Bleeding is a major complication for any type of anticoagulant therapy and can result in a
chronic debilitating condition or death.
2-5
The risk of hemorrhage is often associated with the
intensity of anticoagulation.
6
Another consideration is the increased risk of bleeding with
concomitant treatment such as antiplatelet medication, non-steroidal anti-inflammatory agents
and cyclooxygenase type-2 inhibitors. Depending on the antithrombotic agent and its half-life,
the duration of action can vary from a few hours to several days. When bleeding is life-
threatening or when urgent reversal is required prior to surgery, there may be the need for
reversal. . The risk of bleeding versus thromboembolism must be evaluated for each specific
patient. The optimal approach must take into account patient comorbidities, extent of
anticoagulation and target level of anticoagulation after reversal. Treatment goals include
cessation of bleeding while minimizing the risk of untoward thrombosis with improvement in
clinical outcome.

Inherent limitations in non-randomized, non-comparator trials must be considered while
examining the evidence. Over time, natural hemostasis is expected in hemorrhagic injury. Thus
non-randomized, non-comparator case studies reporting reduction or cessation of bleeding after
administration of procoagulants must be interpreted with caution, as the influence of time cannot
be assessed without a comparator, and the true influence of the administered reversal agent
cannot be accurately assessed.
Recommendations

Oral Anticoagulants: Listed by drug class

Vitamin K Antagonist (i.e. Warfarin)
Warfarin inhibits the activation of vitamin K dependent clotting factors II, VII, IX and X by
inhibiting two specific enzymes, vitamin K epoxide reductase (VKOR) and vitamin K
1
reductase,
and blocking the production of pharmacologically active vitamin K clotting factors. The incidence
of hemorrhagic events associated with warfarin therapy is based on target INR, duration of
therapy, use on concomitant antiplatelet therapy, patient factors, and quality of monitoring.
6-8

Patient factors such as prior history of bleeding, advanced age, cancer, renal or hepatic
insufficiency, arterial hypertension, prior stroke and alcohol abuse are associated with a higher
risk of hemorrhage.
6,9-11
The rate of hemorrhage increases markedly in patients with an INR
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greater than 4.5.
12
Bleeding or potential bleeding of patients on warfarin can be managed by
holding warfarin doses, administering phytonadione, plasma and/or PCC. The approach to
treatment is predicated on the indication for warfarin, location of the bleed, extent of bleeding
and INR (Appendix B).
2
For further information on warfarin treatment, see UW Health Warfarin
Management - Adult - Ambulatory - Clinical Practice Guideline or UW Health Warfarin
Management - Adult - Inpatient Clinical Practice Guideline.


1. The INR and either the extent of bleeding or timing of surgical intervention should be used to
determine the level of warfarin reversal.
2
Table 2 provides common clinical scenarios and
reversal options. (UW Health high quality of evidence, strong recommendation)


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Table 2. Considerations for Warfarin Reversal Based on Clinical Scenario
Clinical Scenario Reversal Strategy Recheck INR Other Considerations
INR 4.5 – 9.9 with NO
significant bleeding
Omit 1-2 doses of warfarin 24–48 hours For high INR no difference
in incidence of bleeding
was seen between
patients treated with
phytonadione versus
placebo
7


INR > 9.9 with NO
significant bleeding

Omit warfarin until INR is near
or within target range

Phytonadione 1 – 2.5 mg
orally (preferred) or IV

24 hours
Any INR with non-major
bleeding
Omit 1-2 doses of warfarin
May consider:
Phytonadione 1 - 5 mg orally
(preferred) or IV
24–48 hours



Dose phytonadione based
on INR, risk of thrombosis,
and extent of bleeding

Any INR with major or life
threatening bleeding

Stop warfarin until bleeding
controlled

Phytonadione 5-10 mg IV
AND
PCC dose based on INR

30 mins after
PCC dose

Administer each agent as
soon as it is available.

There is no specific order
of administration
13

Any INR with need for
reversal for planned
procedure (> 24 hours)
Omit warfarin

May consider based on timing:
Phytonadione 5 mg IV
12 hours If INR remains elevated
then may consider
repeating phytonadione
dose or checking INR prior
to surgery
Any INR with need for
reversal for emergent
surgery (< 24 hours)
Stop warfarin until safe to
resume post-operatively

PCC dose based on INR

May consider:
Phytonadione 5-10 mg IV if not
planning to resume warfarin
immediately post-operatively

30 mins after
PCC dose
If expected length of
surgery > 6 hours,
phytonadione should be
administered with PCC

2. It is reasonable to administer PCC (at dosing listed in Table 3) with or without phytonadione
for patients requiring warfarin reversal prior to emergency surgery or major invasive
procedures.
14,15
(UW Health moderate level of evidence, weak/conditional recommendation)
2.1. There is data to support the use of low fixed dosed PCC for warfarin reversal. See
Appendix F for literature summary. In the literature the majority of patients achieved
the targeted INR goal after low dose PCC was administered without the need for
supplemental PCC dosing. Failure to hit target INR goals were more commonly seen
when the INR was > 6.0.
16-23
(UW Health moderate level of evidence, weak/conditional
recommendation)
2.2. If a patient is HIT positive, but more than 3 months ago, PCC can be administered
(despite heparin content in PCC). If HIT was diagnosed less than 3 months ago
evaluate benefit of procoagulant use versus risk of repeat HIT.
24
(UW Health very low
level of evidence, weak/conditional recommendation)

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Table 3. Prothrombin Complex Concentrate Dosing for Warfarin Reversal
16-23
(UW Health
moderate level of evidence, weak/conditional recommendation)
Pre-Treatment INR Dose of PCC Recheck INR
< 6.0 1000 units 15 – 30 mins after dose
> 6.1 2000 units 15 – 30 mins after dose
Any INR with CNS bleed 2000 units 15 – 30 mins after dose
May repeat with 500 units if INR goal or clinical outcome is not achieved

3. Routine use of FFP for reversal of INR or warfarin-related hemorrhage should be limited.
(UW Health low level of evidence, weak/conditional recommendation)
3.1. Studies have shown FFP fails to consistently reach the target INR goal when
compared to PCC for INR reversal.
25-29

3.2. FFP is associated with higher fluid volumes per dose and transfusion related acute
lung injury (TRALI)
30

3.3. FFP may be used for emergent partial INR reversal (i.e. INR goal < 2) or when large
volumes of blood are being replaced.
31
(UW Health low level of evidence, weak/conditional
recommendation)
4. Routine use of Factor 7A for reversal of warfarin-related hemorrhage is not
recommended.
32-34
(UW Health high level of evidence, strong recommendation)


Direct Thrombin Inhibitor (i.e. Dabigatran)
Dabigatran is a reversible, oral direct thrombin inhibitor and an association between dose and
incidence of bleeding is established in patients with atrial fibrillation.
35
Unlike warfarin,
anticoagulation occurs through inhibition of factor II (thrombin), not depletion of the clotting
factors. The half-life is 12 to 17 hours (in patients with normal renal function) and within 24
hours of stopping dabigatran, concentrations are reduced by approximately 75% of the original
concentration in patients with normal renal function. Due to the short duration of effect,
discontinuation of dabigatran could be sufficient to mitigate anticoagulant effects.
2,36


1. The time of last dose, renal function, and either the extent of bleeding or time to surgical
intervention should be used to determine the level of reversal needed. Table 4 provides
common clinical scenarios and reversal options. (UW Health moderate level of evidence,
weak/conditional recommendation)


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Table 4. Considerations for Dabigatran Reversal Based on Clinical Scenario
37-39
(UW Health
moderate level of evidence, weak/conditional recommendation)
Clinical Scenario Reversal Strategy Lab
Monitoring
Other Considerations
Minor or non-clinically
relevant bleeding
Hold dabigatran N/A Within 24 hours of
stopping, dabigatran
concentrations are
reduced by 75% in
normal renal function
Major or Life
Threatening Bleeding
Hold dabigatran

If dose taken < 12 hrs (normal renal
function): Idarucizumab

If dose taken > 12 hrs, if last dose
unknown or renal insufficiency then
check TT:
• If TT > 25 secs: Idarucizumab

• If TT < 25 secs: no reversal
needed
Creatinine

Thrombin Time
(TT)






Planned Surgery Hold dabigatran
UW Health Periprocedural and
Regional Anesthesia Management
with Antithrombotic Therapy – Adult
– Inpatient/Ambulatory Clinical
Practice Guideline
Creatinine
(at least 7
days prior)

Emergent Surgery Hold dabigatran

If dose taken < 12 hrs (normal renal
function): Idarucizumab

If dose taken > 12 hrs, if last dose
unknown or renal insufficiency then
check TT:
• If TT > 25 secs: Idarucizumab

• If TT < 25 secs: no reversal
needed
Creatinine

Thrombin Time
(TT)







Anti-Xa Inhibitors (i.e. apixaban, edoxaban, rivaroxaban)

With oral factor Xa inhibitors, unlike warfarin, anticoagulation occurs through inhibition of factor
Xa, not inhibition of production of clotting factors. No direct reversal agent is available.
Apixaban, edoxaban, and rivaroxaban have relatively short half-lives in patients with normal
renal function (apixaban 12 hours, rivaroxaban 5- 9 hours, edoxaban 10-14 hours). The
anticoagulant effect of these agents is minimal in patients 48 hours after ingestion
40-42
The
benefit of coagulation must be weighed with the risk of thrombosis based on time of last dose,
comorbidities, and patient characteristics.

There is data from cross over studies, utilizing healthy volunteers that suggest PCC is effective
in correcting anticoagulation laboratory values. Dosing of PCC in these studies used 25 – 50
units/kg/dose.
43-46
While promising the major limitation to these studies is application to clinical
bleeding outcomes. Limited data exists for use of PCC in bleeding caused by Xa inhibitors.

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Case reports and retrospective reviews show PCC to be effective in managing bleeding in 33-
69% of patients treated. Failure to achieve hemostasis was more commonly seen in ICH.
47-52


Factor 7A was also evaluated in the ex vivo study of healthy volunteers receiving one dose of
rivaroxaban 20 mg and decreased time to reach the maximum concentration of thrombin, but
did not increase thrombin generation potential to the same extent as PCC .
44
There are no data
to recommend for or against use of factor 7A for the treatment of life-threatening bleeding
associated with factor Xa inhibitors.

1. For minor or non-clinically significant bleeding hold Xa inhibitor until bleeding subsides and
it is deemed safe to resume anticoagulation. For planned surgical procedures hold Xa
inhibitor per UW Health Periprocedural and Regional Anesthesia Management with
Antithrombotic Therapy – Adult – Inpatient/Ambulatory Clinical Practice Guideline
recommendations. (UW Health moderate level of evidence, strong recommendation)

2. For major or life-threatening bleeding or the need for emergent surgery PCC may be
considered.
43-52
(UW Health low level of evidence, weak/conditional recommendation)
2.1 Optimum dosing of PCC is unknown; however, doses of 25 – 50 Units/kg
(maximum 5000 units) might be considered
43-52
(UW Health low level of evidence,
weak/conditional recommendation)


Parenteral Anticoagulants: Listed by drug class

Heparinoids (i.e. unfractionated heparin, low molecular weight heparin)
Unfractionated heparin (UFH) binds to anti-thrombin III to enhance the rate of neutralization of
factors II (thrombin) and Xa. Therapeutic doses neutralize thrombin and thereby prevent the
conversion of fibrinogen to fibrin.
53
The half-life is only 60 to 90 minutes therefore; therapeutic
effect is eliminated within three to four hours.

Similar to UFH, the primary anticoagulant activity of low molecular weight heparin (LMWH) (i.e.,
enoxaparin, dalteparin) is through antithrombin inhibition of coagulation factors. However,
LMWH binds to factor Xa to a greater extent than thrombin and exhibits a more predictable dose
response than unfractionated heparin.
53
The risk of bleeding from LMWH correlates with the
extent of anticoagulation, but no established method for total reversal of anticoagulation from
LMWH exists. Protamine will only neutralize thrombin activity and has limited, if any activity, on
anti-factor Xa activity.
54-56


1. The dose, time of last dose and renal function should be used to determine the dose of
protamine needed for reversal. Table 5 provides reversal strategies for UFH and LMWH.
(UW Health high level of evidence, strong recommendation)


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Table 5. Considerations for Protamine in UFH or LMWH Reversal
53, 57-59
(UW Health high level of
evidence, strong recommendation)
Drug Reversal Strategy Monitoring Other Considerations
UFH Protamine 1 mg per 100 units of heparin
administered within last 2 hours
(Max dose 50 mg)
61


Anti-Xa
aPTT
ACT


LMWH If given in last 8 hrs:
Protamine 1 mg per 100 anti-Xa units
(1 mg) of LMWH (Max 50 mg)
39,111


If given > 8 hr but < 12 hr:
Protamine 0.5 mg per 100 anti-Xa units
(1 mg) of LMWH
61

Anti-Xa

In renal insufficiency may
consider protamine use
beyond 12 hours

May consider redosing if
bleeding persists 0.5 mg per
1 mg (max 25 mg)

Insufficient evidence exists to make recommendations for or against the use of Factor 7A in
patients with life-threatening bleeding unresponsive to other therapies. Factor 7A 40mcg/kg
may facilitate bleeding control in patients treated with LMWH.
60
Case reports of life-
threatening bleeding in patients treated with LMWH utilized factor 7A 20-120 mcg/kg to
reverse bleeding.
11861-63



Direct Thrombin Inhibitors (i.e argatroban, bivalirudin)

Argatroban and bivalirudin are parenteral direct thrombin inhibitors.
64,65
There are no established
reversal agents; however the short half-lives (argatroban 45 minutes; bivalirudin 25 minutes)
result in a short duration of anticoagulation action often precluding the need for additional
procoagulant therapy.
53


Factor 7A has theoretical applications in reversing argatroban-associated hemorrhage, though
clinical experience for off-label use is limited and has not demonstrated benefit.
66,67
Although a
report demonstrates factor 7A could overcome argatroban anticoagulation based on normal
thromboelastography, this does not represent recovery of thrombin generation and normalized
coagulation.
68,69
One case report of an infant receiving argatroban failed to demonstrate
hemostasis with factor 7A.
66
Insufficient evidence exists to make recommendations for or
against the use of factor 7A for the treatment of life-threatening bleeding with argatroban.

1. Use supportive measures to control bleeding. Insufficient evidence exists to recommend
factor 7A use in argatroban or bivalirudin related hemorrhage.
66-69
(UW Health very low level
of evidence, weak/conditional recommendation)

Anti-Xa Inhibitor (i.e. fondaparinux)

Fondaparinux is a factor Xa inhibitor with an elimination half-life of 17–21 hours.
70
There is no
established reversal agent for fondaparinux.
53


There is insufficient evidence to recommend for or against treatment of major or life-threatening
bleeding due to fondaparinux with factor 7A.
53,59,69
No clinical trial is available to demonstrate
improved clinical outcomes in patients treated with factor 7A; only case reports are available. In
16 healthy male subjects weighing less than 100 kg treated with 10 mg of fondaparinux, a single
dose of factor 7A 90 mcg/kg reduced the thrombin generation time, activated partial
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12


thromboplastin time, and prothrombin time, and increased the endogenous thrombin potential
within 1.5 hours of administration.
71
Young and colleagues again demonstrated in-vitro reversal
of fondaparinux-induced anticoagulation with factor 7A using concentrations the authors
anticipate would be achieved with factor 7A dosing of 90-270 mcg/kg.
68
Reversal of clinically-
significant bleeding from fondaparinux has not been clearly demonstrated with factor 7A, though
a case report notes management of fondaparinux-associated intracerebral hemorrhage with
factor 7A administration (90 mcg/kg x 1) and neurosurgical evacuation.
59
The authors indicated
hemostasis was achieved; however, the patient did not survive.

1. For major or life-threatening bleeding factor 7A may be considered.
59,68,71
(UW Health low
level of evidence, weak/conditional recommendation)

2. Protamine is not effective for the treatment of bleeding associated with fondaparinux.
53
(UW
Health low level of evidence, strong recommendation)

Antiplatelets
There are several classes of antiplatelet agents available: cyclo-oxygenase inhibitors (COX-
inhibitors): i.e. aspirin, ibuprofen, naproxen; P2Y12 ADP receptor inhibitors (i.e. clopidogrel,
prasugrel, ticagrelor, ticlopidine); phosphodiesterase inhibitor (i.e. cilostazol) and glycoprotein
IIb/IIIa inhibitors (i.e. eptifibatide, abciximab). Antiplatelets associated with a higher level of
platelet inhibition are suspected to cause higher incidence of ICH, ICH volume growth, need for
craniotomy and mortality. There is no specific antidote for antiplatelet agents. In general, platelet
function is restored after 3-5 half-lives of a reversible antiplatelet and not until new platelets are
regenerated for irreversible antiplatelets. This can influence the approach to antiplatelet
reversal.
72-74
For recommendations on reversal for planned procedures see: UW Health
Periprocedural and Regional Anesthesia Management with Antithrombotic Therapy – Adult –
Inpatient/Ambulatory Clinical Practice Guideline.

When considering reversal options for antiplatelet agents it is important to consider the severity
of bleeding and if it demonstrates reversible or irreversible antiplatelet effect. General
recommendations for antiplatelets include
72,75
:

1. Reversal of antiplatelets is usually only recommended in life threatening bleeding (i.e.
intracranial hemorrhage). (UW Health moderate level of evidence, strong recommendation)

2. Supportive measures should be used to help manage bleeding. (UW Health low level of
evidence, weak/conditional recommendation)

3. Surgical procedures should be delayed, when possible but if emergent surgery is needed
then supportive measures intraoperatively can be used for managing bleeding (UW Health
low level of evidence, weak/conditional recommendation)


Cyclo-oxygenase inhibitor (COX-inhibitors): i.e. aspirin, ibuprofen, naproxen
Non-selective cox-inhibitors prevent the conversion of arachidonic acid to thromboxane A
2
, thus
inhibiting platelet activation and aggregation. Aspirin causes irreversible inhibition of platelet
aggregation. The effect of aspirin can last 5-7 days after discontinuation. Other non-steroidal
anti-inflammatory drugs (NSAIDs) inhibit COX with a reversible dose dependent effect. As the
drug concentration decreases, COX activity returns. The effect is dependent on the elimination
half-life of each drug.
72,76


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13


Aspirin
There is some data to suggest platelet transfusion can be used in patients with intracranial
hemorrhage undergoing craniotomy. In one randomized, controlled trial, patients who received
platelet transfusion experienced less intraparenchymal hemorrhage recurrence, lower post-
operative hematoma volume, and decreased mortality.
77


The PATCH trial studied platelet transfusion for intracerebral hemorrhage associated with
antiplatelet use. All antiplatelets were included, but COX inhibitor monotherapy represented the
largest antiplatelet therapy in both groups (73% in transfusion and 84% standard care). Patients
who underwent surgical evacuation within 24 hours of admission were excluded. The results
showed platelet transfusions associated with worsening outcomes regarding functional status
and death and no change in volume growth.
78


1. Intracranial hemorrhage undergoing surgical evacuation (i.e. craniotomy) platelet
transfusion may be considered
72,77,78
(UW Health low level of evidence, weak/conditional
recommendation)
1.1. Allow 3-5 half lives of the implicated antiplatelet agent to elapse before attempting
to infuse platelets. This will minimize pharmacologic inhibition of the transfused
platelets.
72
(UW Health low level of evidence, weak/conditional recommendation)

2. Intracranial hemorrhage without surgical evacuation platelet transfusion is not
recommended.
72,77,78
(UW Health low level of evidence, weak/conditional recommendation)

While not well studied, desmopressin (DDAVP) may be considered. A single dose of DDAVP
was used in patients on aspirin undergoing CABG. The DDAVP group resulted in less chest
tube output and total blood loss but no difference in transfusion requirements.
79
Another study
used two doses of DDVAP in open cholecystectomy. It demonstrated shortened bleeding time
when compared to placebo.
80
Another study in intracranial hemorrhage showed platelet
stabilization through platelet function measurements with a single dose, although effect only
lasted 3 hours.
81


3. Intracranial hemorrhage may consider DDAVP 0.4 mcg/kg
72,79-81
(UW Health low level of
evidence, weak/conditional recommendation)
3.1. DDAVP can be used in addition to platelet transfusion
72
(UW Health low level of
evidence, weak/conditional recommendation)

NSAIDs (i.e. ibuprofen, naproxen)
Due to the reversible platelet inhibition and short half-life of most NSAIDs, there is not an
established role for using specific reversal agents.
72

1. Use supportive measures to control bleeding. Insufficient evidence exists to recommend
platelet transfusion or DDVAP to treat related hemorrhage.
72
(UW Health low level of evidence,
weak/conditional recommendation)


P2Y12 ADP Receptor Antagonists (i.e. clopidogrel, prasugrel, ticagrelor, ticlopidine)
Platelet inhibition occurs by binding to the adenosine diphosphate (ADP) receptor on platelets
and preventing activation. This inhibition is irreversible and the effect is present until the drug is
eliminated and new platelets are generated.
82,83
The exception is with ticagrelor which
reversibly inhibits platelet action.
82


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14


The use of platelet transfusion for reversal remains controversial. A single-center prospective,
observational study with IPH and decreased platelet function due either to aspirin or clopidogrel.
Platelet transfusion was associated with smaller hemorrhage size, however, there was no
control group and different transfusion doses were given. Other studies have failed to show
benefit in mortality, hemorrhage growth, or patient functionality from platelet transfusion.
84-86


The PATCH trial studied platelet transfusion for intracerebral hemorrhage associated with
antiplatelet use. All antiplatelets were included, but use of ADP inhibitor either as monotherapy
or combination therapy with a COX inhibitor was not well represented (<4% in both comparator
groups). Patients who underwent surgical evacuation within 24 hours of admission were
excluded. The results showed platelet transfusions associated with worsening outcomes
regarding functional status and death and no change in volume growth.
78


1. Intracranial hemorrhage undergoing surgical evacuation (i.e. craniotomy) platelet
transfusion may be considered
78,84-86
(UW Health low level of evidence, weak/conditional
recommendation)
1.1. Allow 3-5 half lives of the implicated antiplatelet agent to elapse before attempting
to infuse platelets. This will minimize pharmacologic inhibition of the transfused
platelets.
72
(UW Health low level of evidence, weak/conditional recommendation)

2. Intracranial hemorrhage without surgical evacuation platelet transfusion is not
recommended.
78,84-86
(UW Health low level of evidence, weak/conditional recommendation)

DDAVP has not been well studied to control bleeding from P2Y12 ADP inhibitors. A case report
showed transient restoration of platelet function after single dose DDAVP
87
. In healthy subjects,
DDAVP showed improvements in bleeding time and platelet function tests.
88,89


3. Intracranial hemorrhage may consider DDAVP 0.4 mcg/kg
72,87-89
(UW Health low level of
evidence, weak/conditional recommendation)
3.2 DDAVP can be used in addition to platelet transfusion
72
(UW Health low level of
evidence, weak/conditional recommendation)


Phosphodiesterase Inhibitor (i.e. cilostazol)
Phosphodiesterase inhibitors reversibly inhibit platelet aggregation. Due to the reversible
platelet inhibition and relatively short half-life, there is not a role for using specific reversal
agents.
72


1. Use supportive measures to control bleeding. Insufficient evidence exists to recommend
platelet transfusion or DDVAP to treat related hemorrhage
72
(UW Health low level of evidence,
weak/conditional recommendation)

Glycoprotein IIb/IIIa Inhibitors (i.e. eptifibatide, abciximab)
Platelet inhibition occurs through the blocking of the platelet glycoprotein IIb/IIIa receptor and
reversibly inhibiting platelet aggregation. Due to the short half-life of these medications, platelet
function returns within 4-8 hours after discontinuation. There is no specific reversal agent
available.
90


1. Use supportive measures to control bleeding. Insufficient evidence exists to recommend
platelet transfusion or DDVAP to treat related hemorrhage.
72
(UW Health low level of
evidence, weak/conditional recommendation)
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15


UW Health Implementation
Potential Benefits:
• Standardized approach to antithrombotic reversal
• Recommendations for antithrombotics where data is limited

Potential Harms:
• Limited literature for some antithrombotic agents
• Risks for continued bleeding if reversal not complete
• Risks for thrombotic event after reversal

Qualifying Statements: Most studies evaluating procoagulant use in bleeding patients are
small and/or case series or conducted in normal volunteers. Recommendations are subject to
change with the publication of clinical trials and FDA approval of additional agents.

Pertinent UW Health Policies & Procedures
1. Pharmacy Operating Procedure for the Emergent Use of Factor 7A (NovoSeven®)
2. Pharmacy Operating Procedure for the Emergent Use Prothrombin Complex
Concentrate (PCC)

Patient Resources
Not applicable

Guideline Metrics
1. Metric #1: Use of appropriate agent and dosing strategy for each antithrombotic
2. Metric #2: Successful reversal
3. Metric #3: Thrombotic event post reversal

Implementation Plan/Clinical Tools
1. Guideline will be posted on uConnect in a dedicated location for Clinical Practice Guidelines.
2. Release of the guideline will be advertised in the Physician/APP Briefing newsletter.
3. Content and hyperlinks within clinical tools, documents, or Health Link related to the
guideline recommendations (such as the following) will be reviewed for consistency and
modified as appropriate.

Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.
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16


Appendix A. GRADE Methodology adapted by UW Health


GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate
We are quite confident that the effect in the study is close to the true effect, but it
is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations For or Against Practice
Strong
The net benefit of the treatment is clear, patient values and circumstances
are unlikely to affect the decision.
Weak/conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.
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17


Appendix B. Treatment of Bleeding Associated with Oral Anticoagulants




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18


Appendix C. Treatment of Bleeding Associated with Parenteral Anticoagulants
Anticoagulant Usual Half-life Reversal Agent / Bleeding Treatment Comments
Lab
Monitoring
In all cases of substantial bleeding supportive strategies by means of discontinuation of anticoagulant, mechanical compression and administration of
blood products, fluid resuscitation, hemodynamic and respiratory support are required. In addition maintain normal body temperature, blood pH and
electrolyte balance to facilitate coagulation. (See
Argatroban IV 45 min General supportive measures


aPTT
Bivalirudin IV 25 min General supportive measures
aPTT
Fondaparinux
Subcutaneous
17-21 h General supportive measures
. anti-Xa
Heparin IV 1 - 1.5 h
• Protamine 1 mg per100 units of heparin administered
within the last 2 hours. Maximum dose 50 mg.

• Consider monitoring trends in anti-Xa or ACT to
determine requirement for subsequent protamine
dosing
- high doses of protamine
can enhance
anticoagulation
-administer protamine
over 10 minutes
-protamine can cause
anaphylaxis
anti-Xa
ACT
LMWH
Subcutaneous
(e.g., enoxaparin,
dalteparin)

3 -5 h
Time of Last Dose Treatment Measures
Within last 8 h
Protamine 1 mg/100 anti-Xa units
(maximum 50 mg)
- If patient has renal
insufficiency consider
wider timeline for
administering protamine
anti-Xa
If bleeding continues, repeat
protamine 0.5 mg/100 anti-Xa
units (maximum 25 mg)
8 – 12 h ago
Protamine 0.5 mg/ 100 units anti-
Xa units (maximum 50mg)
Dose > 12 h ago Protamine may not be necessary




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19


Appendix D – Treatment of Life Threatening Bleeding Associated with Anticoagulants





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20


Appendix E – Administration Rate of Intravenous Procoagulant Agents
(See also Intravenous Administration Guideline – Adult – Inpatient/Ambulatory Clinical Practice Guideline
Medication Rate of Administration
Desmopressin Over 20 – 30 minutes
Factor 7A Over 2 minutes
Idarucizumab Over 10 - 20 minutes
Phytonadione Over 20 – 30 minutes
Protamine 10 mg over 1 – 3minutes, 50 mg over 10 minutes minimum
Prothrombin Complex Concentrate
(PCC)
100 units/minute, maximum 200 units/minute

Appendix F – Literature Summary for Low Fixed Dose PCC
Reference Patient Population PCC Type N PCC Dose INR Goal INR Outcome
Achieved
Comments
Abdoellakhan R, 2017 Warfarin reversal for
ICH
4 Factor
(Cofact)
N = 28
N = 25
Fixed dose 1000 IU
Weight based (WB)
<1.5 68% FD

96% WB
Mean dose WB: 1750 IU
Median INR: 3.1 (WB) and 3.3 (FD)
Per study FD may have been too low for ICH
bleeding
Kantorovich A, 2015 Heart transplant
surgery
3 Factor N = 16 INR < 3.5: 10 units/kg
INR > 3.5: 20 units/kg
< 1.7 75% Median INR 2.46 (2.2-2.9)
Average weight 80.8 kg
Higher percentage of patients received the 20
units/kg dose
Klein L, 2015 Warfarin reversal for
any reason
4 Factor
(Kcentra)
N = 39 Fixed dose 1500 IU < 2.0

<1.5
92.3%

71.8%
Average weight 79.5 kg
Median INR: 3.3 (2.5-4.0)
Second dose needed in 1 patient

Quick JA, 2015 Acute care surgery 3 Factor N = 41 15 units/kg < 1.5 78% Median INR 2.52
Higher percentage of failure seen with INR > 4.3
Hirri HM, 2014 Warfarin reversal for
any reason
4 Factor
(Octaplex)
N = 67 CNS bleeds 2000 IU
Other bleeds 1500 IU
Non-bleeding 1000 IU
<1.5 83.6% Higher percentage of failure seen with INR > 6
None needed a second dose
Varga C, 2013 Warfarin reversal for
any reason
4 Factor
(Octaplex)
N = 103 1000 IU <1.5
< 2.0
48.5%
92.2%
Median INR: 2.8 (1.4 – 24)
Higher INR may require higher PCC dosing (not clear
in study the definition of higher INR)
Khorsand N, 2012 Warfarin reversal for
any reason (except
ICH)
4 Factor N = 101
N = 139
Fixed dose 1040 IU
Weight based (WB)
< 2.0 92% FD
95% WB
Median INR FD 5.1 and WB 5.9
Higher percentage of failure seen with INR > 7.5
Khorsand N, 2011 Warfarin reversal for
any reason (except
ICH)
4 Factor
(Cofact)
N = 35
N = 32
1040 IU for bleeding
520 IU for procedure reversal
<1.5
<2.0
(if epidural use < 1.8)
70%
81%
Median INR: 4.7 (2.0 - > 9.0)
Higher percentage of failure seen with INR > 5
Clinical outcomes achieved 91% and 94%
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21


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Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 01/2018CCKM@uwhealth.org