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Reversal of Newer Anticoagulants

Andria F. Brantley, Pharm.D.

PGY-1 Pharmacy Practice Resident

Memorial Hospital Pembroke

Residency Director: Shalonda Barnes-Warren, Pharm.D., BCPS

www.fshp.org

Disclosure

• I have no conflicts of interests to declare regarding the content of this presentation.

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Objectives• Pharmacists

I. Compare and contrast mechanisms, roles in therapy, and adverse effect profiles of the new oral anticoagulants

II. Summarize available evidence based literature for the reversal of the new oral anticoagulants

III. Select the most appropriate agent for reversal of new oral anticoagulants in clinical practice

• Technicians

I. Identify brand/generic names of newer anticoagulants

II. State the common conditions that newer anticoagulants are used to manage

III. Explain the common adverse effects of anticoagulants

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Epidemiology1,2

• Venous thrombosis embolism (VTE) defined as deep vein thrombosis and pulmonary embolism (DVT/PE)

• Affects an estimated 300,000-600,000 individuals in the U.S. annually

• Frequency of VTE increases with age

– 1 in 100 in those 80 years or older

• Overall rate is higher among African Americans and Caucasians

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Blood Clot Formation

5

Epidemiology3,4,5

• Atrial Fibrillation

– Structural/electrical abnormalities that change atrial tissue and cause abnormal impulse formation

• Affects an estimated 2.7-6.1 million people in the United States

– Causes 15%-20% of ischemic strokes

• Incidence increases with age

– 1 in 4 adults 40 years or older

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Atrial Fibrillation

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Epidemiology1,2,3

• Morbidity and mortality

– Approximately 60,000-100,000 Americans die of DVT/PE annually

• 10-30% die within one month of DVT diagnosis

• Sudden death occurs in 25% of PE patients

– One-half of PE patients have long-term complications

– Following anticoagulation therapy about 1/3 of patients have a recurrence in10 years

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Clotting Cascade for New Oral Anticoagulants

F: Factor, T*: Thrombin

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Table 1: FDA Approved Indications for New Oral Anticoagulants (NOAC) 6,7,8,9

FDA IndicationsPradaxa®

(dabigatran)

Xarelto®

(rivaroxaban)

Savaysa®

(edoxaban)

Eliquis®

(apixaban)

Stroke prevention in nonvalvular atrial fibrillation

X X X X

DVT/PE treatment X X X X

Reduction in risk of recurrent DVT/PE after initial therapy after initial therapy

X X - X

DVT prophylaxis following replacement surgery of hip or knee

X X - X

Pill Identification

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Comparison of New Oral Anticoagulants: Metabolism and Bleeding Risk

Comparative Properties of New Oral Anticoagulants 6,7,8,9

Pradaxa®

(dabigatran)

Xarelto®

(rivaroxaban)

Savaysa®

(edoxaban)

Eliquis®

(apixaban)

TargetDirect thrombin

inhibitorFactor Xa Factor Xa Factor Xa

Prodrug Yes No No No

Bioavailability 6.5% >80% 62% 50%

Half-life 14-17 hours 5-9 hours 10-14 hours 10-14 hours

Metabolism Hepatic Hepatic Hepatic Hepatic

Elimination 80% renal 66% renal 50% 27% renal

Plasma protein binding 34-35% 92-95% 55% 87%

Drug InteractionsP-gp inducers/

inhibitorsP-gp inducers/ inhibitors, 3A4

P-gp inducers/ inhibitors, 3A4

P-gp inducers/ inhibitors

P-gp: P-glycoprotein

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Pradaxa® (dabigatran) is not dialyzable, due to its low plasma protein binding.

A) True

B) False

Bleeding Risk of New Oral Anticoagulants

Bleeding Events in Dabigatran Patients with Nonvalvular Atrial Fibrillation

RE-LY Trial 10

Dabigatran 150mg

twice daily

n=6076

Warfarin

n=6022

Relative Risk

(95% CI)P-value

Intracranial

hemorrhage36 (0.59%) 87 (1.44%) 0.40 (0.27-0.60) <0.001

Gastrointestinal 182 (3.0%) 120 (1.99%) 1.50 (1.19-1.89) <0.001

Life-threatening

bleeding175 (2.88%) 212 (3.52%) 0.81 (0.66-0.99) 0.04

Major bleeding 375 (0.617%) 2142 (6.59%) 0.91 (0.86-0.97) 0.002

Minor bleeding 1787 (29.4%) 1931 (32.0%) 0.91 (0.85-0.97) 0.005

Major bleeding: hemoglobin reduction ≥ 20gm/liter, transfusion ≥2 units blood, symptomatic bleeding in a critical area organ; life-threatening bleeding: fatal bleeding, symptomatic intracranial bleeding, bleeding with decrease in hemoglobin ≥50gm/liter, bleeding requiring ≥4 units blood or inotropic agent for necessitating surgery; risk of major bleeding increased with age ≥75 years (HR 1.2, CI 1-1.4);

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Bleeding Risk of New Oral Anticoagulants

Bleeding Events in Rivaroxaban Patients in the Treatment of Symptomatic Venous Thromboembolism

EINSTEIN Trial 11

Rivaroxaban 15mg twice

daily for 21 days, then

20mg daily

n=1731

Enoxaparin/warfarin

n=1718

Hazard Ratio

(95% CI)P-value

Major bleeding 14 (0.8%) 20 (1.2%) 0.65 (0.33-1.3) 0.21

Clinically relevant non-major

bleeding126 (7.3%) 119 (7.0%) -- --

First major or clinically relevant

non-major bleeding occurring

during treatment

139 (8.1%) 138 (8.1%) 0.97 (0.76-1.22) 0.77

Major bleeding: decrease hemoglobin ≥2 gm/dL and/or transfusion ≥2 units blood or both, bleeding in a critical site, contributing to death

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Bleeding Risk of New Oral Anticoagulants

Bleeding Events in Edoxaban Patients in with Nonvalvular Atrial Fibrillation

ENGAGE AF-TIMI Trial 12

Edoxaban 60mg daily

n=7012

Warfarin

n=7012

Hazard Ratio

(95% CI)

P-value

Major bleeding 418 (2.75%) 524 (3.43%) 0.80 (0.71-0.91) <0.001

Intracranial 61 (0.39%) 132 (2.13%) 0.47 (0.34-0.63) <0.001

Gastrointestinal 232 (1.51%) 190 (1.23%) 1.23 (1.02-1.50) 0.03

Life threatening 62 (0.40%) 122 (0.78%) 0.51 (0.38-0.70) <0.001

Minor bleeding 604 (4.12%) 714 (4.89%) 0.84 (0.76-0.94) 0.002

Major bleeding: defined by the International Society on Thrombosis and Haemostasis

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Bleeding Risk of New Oral Anticoagulants

Bleeding Events in Apixaban Patients with Nonvalvular Atrial Fibrillation

ARISTOTLE Trial 13

Apixaban 5mg twice daily

n=9088

Warfarin

n=9052

Hazard Ratio (95% CI) P-value

Major Bleeding 327 (3.6%) 462 (5.1%) 0.69 (0.60-0.80) <0.001

Gastrointestinal 105 (1.16%) 119 (1.31%) 0.89 (0.70-1.15) 0.37

Intracranial 52 (0.57%) 122 (1.35%) 0.42 (0.30-0.58) <0.001

Any bleeding 2356 (25.9%) 3060 (33.8%) 0.71 (0.68-0.75) <0.001

Major bleeding: decrease in hemoglobin of 2gm/dL or transfusion ≥2 units packed red cells, occurring in a critical site or resulting in death

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Reversal Strategies of New Oral Anticoagulants

Principles and Measures for Management of Anticoagulant-related Bleeding 14,15

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General PrinciplesGeneral Principles

•Stop anticoagulant

•Hemodynamic and hemostatic resuscitation

•Volume replacement

•Local hemostatic measures

•Check coagulation tests/platelets/fibrinogen/renal function

•Blood product/coagulation factor/platelet replacement if indicated

•With uncontrollable hemorrhage, use a massive transfusion protocol to keep up with bleeding

Specific MeasuresSpecific Measures

•VKA/Oral Xa inhibitors: PCCs

•Dabigatran: activated charcoal, activated PCCs, hemodialysis, Idarucizumab

Adjunctive MeasuresAdjunctive Measures

•Consider fibrinolyLcs−tranexamic acid

VKA: vitamin K antagonists, PCCs: prothrombin complex concentrate

Reversal Strategies Activated CharcoalActivated Charcoal

Fresh Frozen Plasma (FFP)Fresh Frozen Plasma (FFP)

• Bebulin VH®

• Profilnine SD®

3-Factor Prothrombin Complex Concentrates (3F-PCC)3-Factor Prothrombin Complex Concentrates (3F-PCC)

• Kcentra®

• FEIBA®

4-Factor Prothrombin Complex Concentrates (4F-PCC)4-Factor Prothrombin Complex Concentrates (4F-PCC)

• NovoSeven®

Recombinant Factor VIIa (rFVIIa)Recombinant Factor VIIa (rFVIIa)

• Praxbind® (Idarucizumab)

Humanized Monoclonal AntibodyHumanized Monoclonal Antibody

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Activated Charcoal16

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Indication Acute poisoning

Mechanism Adsorbs toxic substances, thus inhibiting GI absorption and preventing systemic toxicity

Formulation Oral liquidReconstituted suspension

Adverse Reactions Fecal discoloration, constipation, vomiting

Administration Flavoring agents or thickening agents can enhance palatabilityThe container should be agitated, before administration

Onset Depends upon ingestion

Storage and Handling Room temperature

Fresh Frozen Plasma17

• Restores all coagulation factors

• Contains coagulation factors in normal serum concentrations

– Significantly lower amounts of clotting factors II, VII, IX, and X

• Must be thawed, ABO type matching required, large volume of administration

– Dose: 10-20mL/kg

• Associated with fluid overload, infectious disease, transfusion related acute lung injury

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Prothrombin Complex Concentrates (PCC)

Prothrombin Complex Concentrates18,19

• Concentrated plasma products that contain clotting factors in varying amounts

– Formulations can include:

• 3-Factor products (II, IX, and X)

• 4-Factor products (II, VII, IX, and X)

• May also contain coagulation inhibitors to mitigate thrombotic risk

• Proposed mechanism for reversal: large amounts of factor X may decrease inhibitory effects of factor Xa inhibitors

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Bebulin®/ Profilnine®20,21

Indication Control and prevention of bleeding episodes in adult patients with hemophilia B; Warfarin associated hemorrhage

Mechanism Replaces deficient clotting factor including factor X

Formulation Bebulin® •Reconstituted solution•Contains factors II, IX, X, and low levels of VII and heparin

Profilnine SD® •Reconstituted solution•Contains factors II, IX, X, and low levels of VII

Adverse Reactions Nausea/vomiting, headache, fever, thrombosis, somnolence, pyrexia, chills, hypotension and DIC

Preparation Reconstitute with diluent provided with kit

Administration Solution should be infused at room temperatureRate should not exceed 2 mL/minute for Bebulin or 10 mL/minute for Profilnine

Onset Less than 30 minutes

Storage and Handling Store at refrigerated temperature. Do not freeze

FDA Approval Bebulin® April 7, 2011

Profilnine SD® July 20, 1981 25

Kcentra®22

Indication Urgent reversal of acquired coagulation factor deficiency induced vitamin K antagonist therapy in adult patients with acute

major bleeding

Mechanism Prothrombin complex concentrate provides an increase in the levels of the vitamin K-dependent coagulation factors (II, VII, IX, and X) with the addition of protein C and protein S.

Formulation Reconstituted solutionContains clotting factors II, VII, IX, and X, proteins C and S

Adverse Reactions Headache, nausea/vomiting, arthralgia, and hypotension

Preparation Reconstitute with 20mL of diluent provided with kit

Administration Administer at room temperature at a rate of 0.12 mL/kg/minute (~3 units/kg/minute); do not exceed 8.4 mL/minute (~210 units/minute). Do not allow blood to enter into syringe; Must be used within 4 hours of reconstitution

Onset Rapid; significant INR decline within 10 minutes

Storage and Handling Store between 20-250 C. Do not freeze

FDA Approval April 29, 2013

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ISMP Alert23

• Misleading label leads to dosage errors

– Base dosing on actual potency

– Varies from 20-31 Factor IX units/mL

– Normal potency is ~500 units per vial

27“Safety requires a state of mindfulness”

Fresh frozen plasma is associated with transfusion related acute lung injury.

A) True

B) False

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Activated Prothrombin Complex Concentrate (aPCC)

FEIBA®23

Indication Spontaneous bleeding episodes or surgical interventions in hemophilia A and B patients

Mechanism Multiple interactions of the components in FEIBA restore the impaired thrombin generation of hemophilia patients with inhibitors. Shortens aPTT of plasma containing Factor VII inhibitor

Formulation Reconstituted solution500 units; 1000 units; 2500 units

Adverse Reactions Anemia, diarrhea, hepatitis B antibody positive

Preparation Reconstitute with 20mL or 50mL of diluent provided with kitWhite, off white or pale green freeze dried powder

Administration IV injection or drip infusion only; maximum infusion rate: 2 units/kg/minute. Following reconstitution, complete infusion within 3 hours.

Onset Rapid (peak at 15-30minutes)

Storage and Handling Store at room temperature. Do not freeze

FDA Approval May 27, 2009

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Novoseven RT®24

Indication Indicated for the treatment of bleeding episodes and perioperative management in adults and children with hemophilia A or

B, congenital Factor VII deficiency, Glanzmann’s

Mechanism Replaces deficient activated coagulation factor VII

Formulation Reconstituted solution1mg; 2mg; 5mg; 8mgContains activated factor VII

Adverse Reactions Thrombotic events, were most common in clinical trials

Preparation Reconstitute with diluent provided

Administration IV administration only as a bolus over 2 to 5 minutesAdminister within 3 hours after reconstitution

Onset Less than 30 minutes

Storage and Handling Prior to reconstitution store between 20-250 C. Do not freeze.

FDA Approval August 6, 2010

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Prothrombin Complex Concentrates and Hemophilia Agent Composition18,19

Brand Names Components Dose Time to Effect (min) Duration

(hr)

Cost

(AWP)

3F-PCC Bebulin Factors II, IX, X, low concentration factor VII,

heparin

25-90 units/kg 10 6-8 $1.14 /IU

Profilnine SD Factors II, IX, X, and low concentration factor VII

20-50 units/kg 10 6-8 $1.19 /IU

Activated 4F-PCC FEIBA Factors II, VII, IX, X 50-100 units/kg 15 8-12 $2.17 /IU

Kcentra Factors II, VII, IX, X, proteins C/S, antithrombin

25-50 units/kg 15 6-8 $2.17 /IU

rFVIIa NovoSeven RT Activated rFVIIa 15-90 mcg/kg 10 <1 $1.64/ mcg

AWP: average wholesale price, IU: international units

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Trials Patients Treatment 1◦ endpoint Results

Apixaban Induced Alterations in

Hemostasis by different

coagulation factor concentrates

PlosONE.20013;8(11): e78696

10 healthy volunteers rFVIIa (Novoseven) 270 μg/kg

aPCC (FEIBA) 75 U/kg

4F-PCC (Beriplex) 50 IU/kg

Clotting assays, measure TG, CFT, thrombin peak, lag phase, time peak to determine reversal

rVIIa and aPCC normalized prolongation to reach peak TG,

rVIIa/aPCC signifcantly reversed lag phase and thrombin peak (p<0.01),

rVIIa/aPCC significantly reduced CT and CFT (p<0.01)

aPCC shows potential and may be 1st

line

Impact of 3F-PCC on

anticoagulatory effects of

Edoxaban

Thrombosis Research 136(2015)

825-831

24 healthy volunteers Single-dose 60mg or single-dose 180mg of Edoxaban, followed by placebo or25 IU/kg 3F-PCC or 50 IU/kg 3F-PCC

Evaluate reversal of 25-50 IU/kg doses of 3F-PCC using prothrombin time as the primary PD maker and ETP

No apparent reversal of PT prolongation, but ETP was completely

reversed

Reversal of Rivaroxaban and

Dabigatranby PCC

Circulation. 2011;124:1573-1579

12 healthy male volunteers Dabigatran 150mg twice daily or Rivaroxaban 20mg twice daily for 2.5 days

Received either PCC 50 IU/kg or Saline on Day 3

Reversal of anticoagulant effect by measuring PT and ETP (rivaroxaban) and APTT, ETP, lag time, thrombin time, ecarinclotting time (dabigatran)

Rivaroxaban: PCC completely reversed prothrombin time (12.8±1.0; p<0.001),

and normalized ETP (114±26; p<0.001)

Dabigatran: 4F-PCC did not significantly reverse aPTT, ETP lag time, thrombin time, ecarin clotting time

Reversal of Rivaroxaban induced

anticoagulation by PCC, aPCC,

and rFVIIa

Thromb Res. 2014;133:671-681

Healthy volunteers Rivaroxaban diluted to simulate a 20mg dose and hypothetical over dose

aPCC (FEIBA) 0.2 U/mL, 0.4 U/mL, 0.7 U/mL

4F-PCC (Beriplex) 0.4 U/mL, 0.2 U/mL, 0.7 U/mL

rFVIIa (Novoseven 5μg/mL, 15μg/mL, 50μg/mL

Reversal of anticoagulant effects by measuring PT, CT, TG lag time, maximum concentration, ETP

PCC : decreased prothrombin time by

15-20% (p<0.001)

aPCC/rFVIIa significantly shortened

clotting time (p<0.001)

aPCC/rFVIIa significantly reversed lag

time (p<0.001)

PCC significantly reversed ETP(p<0.01)

aPCC significantly increased ETP (p<0.01)

TG: thrombin generation, CT: clotting time, CFT: clot formation time, MCF: maximum clot firmness, PD: pharmacodynamic, PT: prothrombin time, ETP: endogenous thrombin potential

Kcentra® has a normal potency of ~500 units per vial, but has varying amounts of Factor IX

from 20-31 units/mL.

A) True

B) False

Humanized Monoclonal Antibody

Praxbind® (idarucizumab)25

Indication Emergency surgery/urgent procedures or in life-threatening or uncontrolled bleeding

Mechanism Binds to dabigatran and its acylglucuronide metabolites with higher affinity and neutralizes the anticoagulant effect

Formulation Sterile, preservative free, colorless to slightly yellow, clear to slightly opalescent solution available as:Injection: 2.5g/mL solution in a single use vial

Adverse Reactions Headache, hypokalemia, delirium, constipation, pyrexia, and pneumonia

Preparation Once solution has been removed from the vial, administration should begin promptly or within 1 hour

Administration The recommended dose of Praxbind is 5g provided as two separate vials containing 2.5g/50mL Idarucizumab.In clinical trials Idarucizumab was administered as one 5g intravenous infusion over 5 minutes.

Onset Immediate and sustained for 24 hours

Storage and Handling Store in the refrigerator. Do not freeze or shake.

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Idarucizumab for Dabigatran Reversal RE-VERSE AD Trial27

Purpose Examine efficacy and safety of idarucizumab for dabigatran reversal

Design Multicenter, prospective cohort studyInterim analysis, data on 90 of 300 patientsEach patient received two 2.5 g infusions 15 minutes apart

Patients 18 years and older and on dabigatranGroup A: Life-threatening bleedGroup B: Urgent surgery or procedure required

End Points Primary:• Maximum percentage reversal

Secondary:• Proportion with normalization of dilute thrombin time• Proportion with normalization of ecarin clotting time• Reduction in concentration of unbound dabigatran

Safety: • All adverse events captured

Results 22 patients had dilute thrombin times that were within normal limits and 9 of those patients had normal clotting times excluding these 22 pts from analysis

81 of 90 were assessed with ecarin-clotting time test All patients received idarucizumab regardless of their inclusion in the efficacy analysis

Primary Outcome• Maximum percentage reversal in Groups A and B was 100%

Secondary Outcome• Group A DTT and ECT: 98% and 89% respectively• Group B DTT and ECT: 93% and 88% respectively

ISMP Alert26

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Recommendations for the Reversal of New Oral Anticoagulants

Recommendations for Reversal of New Oral Anticoagulants28,29,30,31,32,33,34,35

Consider additional methods for reversal in minor bleedingConsider additional methods for reversal in minor bleeding

Pradaxa® DabigatranPradaxa® Dabigatran• First Line: Praxbind® Idarucizumab, neutralizes anticoagulant effect

• Second Line: aPCC may be beneficial

Xarelto® RivaroxabanXarelto® Rivaroxaban• First Line: rFVIIa and aPCC are more effective than 4F-PCC for reversal effects

• Second Line: 4F-PCC partially reverses its anticoagulant effect

Savaysa® EdoxabanSavaysa® Edoxaban• First Line: 4F-PCC may be suitable for reversal

• Second Line: 3F-PCC reverses endogenous thrombin potential

Eliquis® ApixabanEliquis® Apixaban• First Line: aPCC partially reversed anticoagulant parameters

• Second Line: rFVIIa partially reversed its anticoagulant effect

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Antidotes Under Development

PER97736

• A small molecule antidote has been shown in preliminary studies to bind directly and specifically to direct thrombin inhibitors, factor Xa inhibitors, and heparins

– Edoxaban required the lowest dose for full reversal

– In a study of 80 healthy volunteers given Edoxaban, PER977 normalized blood clotting time in 10 minutes

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Andexanet alfa37

• A recombinant “decoy” protein of catalytically inactive, truncated form of factor Xa.

• Binds directly to factor Xa inhibitors art subnanomolar affinity

• In a series of 101 healthy volunteers were given apixaban and rivaroxaban, andexanet was effective at reversal within minutes

• A study evaluating efficacy for patients with factor Xa inhibitor-associated bleeding is ongoing

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Clinical Pearls

• Anticoagulation is an important standard therapeutic approach for cardiovascular disease

• Clinical data is very limited, primarily non-human to guide management of bleeding

• The goal for the bleeding patient is to improve the clinical situation

• There are currently 2 novel oral anticoagulant specific reversal agents in clinical development

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References1. Centers for Disease Control and Prevention. Deep vein thrombosis/pulmonary embolism-blood clot forming in a vein. http://www.cdc.gov/ncbddd/dvt/data.html. Updated June 8, 2012. Accessed February 3,

2016.

2. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-69. Centers for Disease Control and Prevention. Atrial Fibrillation fact sheet. http://c.ymcdn.com/sites/

3. www.kphanet.org/resource/resmgr/KnowYourPharmacistResources/Fact_Sheet_atrial_fibrillati.pdf. Updated 2010. Accessed February 3, 2016.

4. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS Guideline for the managements of patients with atrial fibrillation. J Am Coll Cardiol. 2014. doi:10.1016/j.jacc.2014.03.021.

5. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation. CHEST. 2012;141(2 suppl):e531S-e575S.

6. Pradaxa (dabigatran) [package insert]. Ridgefield, CT; Boehringer-ingelheim; Revised September, 2014. https://www.pradaxa.com. Accessed February 3, 2016.

7. Eliquis (apixaban) [package insert]. Princeton, NJ; Bristol-Meyers Squibb; Revised August, 2012. http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed February 3, 2016.

8. Xarelto (rivaroxaban) [package insert]. Titusville, NJ; Jansenn; Revised September, 2014. http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf. Accessed February 3, 2016.

9. Savaysa (edoxaban) [package insert]. Parsippany, NJ; Daiichi Sankyo http://www.savaysahcp.com/sites/default/files/pdf/savaysa_0.pdf. Accessed February 3, 2016.

10. Connolly S, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139-1151.

11. Verhamme, P,. Wells, P., Agnelli, G., Bounameaux. “Oral Rivaroxaban for Symptomatic Venous Thromboembolism.” New England Journal of Medicine N Engl J Med 363.26 (2010): 2499-510. Web. 18 Feb. 2016.

12. Giugliano, Robert P., Christian T. Ruff, Eugene Braunwald, Sabina A. Murphy, Stephen D. Wiviott, Jonathan L. Halperin, Albert L. Waldo, Michael D. Ezekowitz, Jeffrey I. Weitz, Jindřich Špinar, Witold Ruzyllo, Mikhail Ruda, Yukihiro Koretsune, Joshua Betcher, Minggao Shi, Laura T. Grip, Shirali P. Patel, Indravadan Patel, James J. Hanyok, Michele Mercuri, and Elliott M. Antman. "Edoxaban versus Warfarin in Patients with Atrial Fibrillation." New England Journal of Medicine N Engl J Med369.22 (2013): 2093-104.

13. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992.

14. Sarich, Troy C., Jonathan H. Seltzer, Scott D. Berkowitz, James Costin', John T. Curnutte, C. Michael Gibson, Maureane Hoffman, Edvardas Kaminskas, Mitchell W. Krucoff, Jerrold H. Levy, Paul D. Mintz, Paul A. Reilly, Philip T. Sager, Daniel E. Singer, Norman Stockbridge, Jeffrey I. Weitz, and Peter R. Kowey. "Novel Oral Anticoagulants and Reversal Agents: Considerations for Clinical Development." American Heart Journal

169.6 (2015): 751-57. Web. 29 Feb. 2016.

15. Crowther, Mark, and Mark A. Crowther. "Antidotes for Novel Oral Anticoagulants." Arterioscler Thromb Vasc Biol Arteriosclerosis, Thrombosis, and Vascular Biology 35.8 (2015): 1736-745. Web. 29 Feb. 2016.

16. Activated charcoal. In: UpToDate, Waltham, MA. (Accessed on February 28, 2016.)

17. Octaplas [package insert]. Hoboken, NJ: Octapharma USA; 2011.

18. Babilonia, Katrina, and Toby Trujillo. "The Role of Prothrombin Complex Concentrates in Reversal of Target Specific Anticoagulants." Thrombosis Journal Thrombosis J 12.1 (2014): 1-9. Web. 29 Feb. 2016.

19. Kreuziger, Lisa M. Baumann, Joseph C. Keenan, Colleen T. Morton, and David J. Dries. "Management of the Bleeding Patient Receiving New Oral Anticoagulants: A Role for Prothrombin Complex Concentrates." BioMed Research International 2014 (2014): 1-7. Web. 29 Feb. 2016.

20. Bebulin [package insert]. Westlake Village, CA:Baxter; 2012.

21. Profilnine [package insert]. Westlake Village, CA:Baxter; 2012.

22. Kcentra [package insert]. Kankakee, IL:CSL Behring; 2013.

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References23. FEIBA [package insert]. Westlake Village, CA:Baxter; 2011.

24. Novoseven [package insert]. Plainsboro, NJ:Baxter; 2010.

25. Praxbind [package insert]. Ridgefield, CT:Boehringer; 2015.

26. Smetzer, Judy, Micheal Cohen, and Russell Jenkins. "Acute Care ISMP Medication Safety Alert." Institute for Safe Medication Practices. ISMP, 5 November 2015. Web. 1 Mar. 2016

27. Pollack, Charles, Paul Reilly, and John Eikelboom. "Idarucizumab for Dabigatran Reversal — NEJM." New England Journal of Medicine. New England Journal of Medicine, 22 June 2015. Web. 29 Feb. 2016.

28. Zahir, H., K. S. Brown, A. G. Vandell, M. Desai, J.-F. Maa, V. Dishy, B. Lomeli, A. Feussner, W. Feng, L. He, M. A. Grosso, H. J. Lanz, and E. M. Antman. "Edoxaban Effects on Bleeding Following Punch Biopsy and Reversal by a 4-Factor Prothrombin Complex Concentrate." Circulation 131.1 (2014): 82-90. Web. 1 Mar. 2016.

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Thank YouAny Questions?

Andria F. Brantley, Pharm.D.Pharmacy Practice Resident

Memorial Hospital PembrokePharmacy Department

anfrazier@mhs.net954-883-8714