Reversal of New Oral Anticoagulants

http://www.keepcalm-o-matic.co.uk

April Hinds, PharmD

PGY2 Ambulatory Care Resident
Blackstock Family Practice/Community Care Clinic
The University of Texas College of Pharmacy at Austin

October 17, 2014

Learning Objectives:
1. Describe new oral anticoagulants place in therapy
2. Explain the mechanism of action and compare differences between new oral anticoagulants
3. Assess bleeding risk of new oral anticoagulants
4. Summarize current available evidence for the reversal of new oral anticoagulants
5. Recommend agents for reversal of new oral anticoagulants

Hinds 1
I. New oral anticoagulants: place in therapy
A. Epidemiology1,2
i. Deep venous thrombosis/pulmonary embolism (DVT/PE)
1. DVT: formation of a thrombus in the vein
2. PE: when a thrombus is dislodged into the pulmonary circulation and
occludes the pulmonary arteries
3. Approximately 300,000-600,000 affected annually in the U.S.
4. Venous thrombosis frequency increases with age
a. As high as 1 in 100 in those >80 years old
ii. Atrial fibrillation3,4,5
1. Structural/electrical abnormalities that change atrial tissue and cause
abnormal impulse formation
2. Most common type of arrhythmia
3. Estimated occurrence 2.66 million people in 2010
4. Incidence increases with age
a. 1 in 4 adults 40 years
b. Median age of atrial fibrillation diagnosis: 66.8 years for men,
74.6 years for women
2. CHADS2 score used for stroke risk stratification
ii. DVT prophylaxis in knee/hip replacement surgery6
1. 35 day untreated baseline risk for DVT is approximately 4.3%
iii. Morbidity and mortality1,2,5
1. Approximately 60,000-100,000 Americans die of DVT/PE annually
a. 10-30% die within one month of DVT diagnosis
b. Sudden death occurs in 25% of PE patients
2. One-half of PE patients have long-term complications
3. One-third of patients have a recurrent DVT within 10 years
4. Nonvalvular atrial fibrillation can lead to stroke and heart failure
a. Atrial fibrillation causes 15-20% of ischemic strokes
b. Stroke incidence increases based on CHADS2 score
B. New oral anticoagulants: apixaban, dabigatran, rivaroxaban
Table 1: FDA Approved Indications for New Oral Anticoagulants7,8,9
FDA Indications Dabigatran Rivaroxaban Apixaban
DVT/PE treatment and reducing risk of recurrent
X X
DVT/PE after initial therapy
Stroke prevention in nonvalvular atrial
X X X
fibrillation
DVT prophylaxis following replacement surgery
X X
of hip or knee

Hinds 2
 Figure 1: Clotting Cascade and New Oral Anticoagulants10

i. New oral anticoagulants (NOACs) versus warfarin therapy11

1. Reduction in intracranial hemorrhage
2. Bleeding rates similar or lower (0.1-5.6%)
3. More dependent on renal excretion
4. Fixed doses
5. No routine monitoring
6. No major food interactions
II. Comparison of new oral anticoagulants: metabolism and bleeding risk
A. Comparison of agents
Table 2: Comparison of New Oral Anticoagulants7,8,9
Dabigatran Rivaroxaban Apixaban
Target Factor IIa (direct Factor Xa Factor Xa
thrombin inhibitor)
Prodrug Yes No No
Bioavailability 6.5% >80% 50%
Half-life 14-17 hours 5-9 hours 10-14 hours
Metabolism Hepatic Hepatic Hepatic
Elimination 80% renal 66% renal 27% renal
Plasma protein binding 34-35% 92-95% 87%
Drug interactions P-gp inducers/ P-gp inducers/ P-gp inducers/
inhibitors inhibitors, 3A4 inhibitors, 3A4
P-gp: P-glycoprotein; see Appendix A for additional information, pg 18
B. Bleeding risk of new oral anticoagulants
i. Dabigatran12
1. Statistically significant higher bleeding rates for life-threatening
bleeding and minor bleeding in warfarin group versus dabigatran
2. Statistically significant higher bleeding rates for gastrointestinal
bleeding in dabigatran group versus warfarin
3. No significant difference between bleeding rates for intracranial
hemorrhage or major bleeding in dabigatran group versus warfarin

Hinds 3
 Table 3: Bleeding Events in Dabigatran vs Warfarin12
Dabigatran 150 Warfarin Relative Risk P-value NNH
mg twice daily (n=6022) (%) (95% CI)
(n=6076) (%)
Intracranial hemorrhage 36 (0.59) 87 (1.44) 0.40(0.27-0.60) 0.38 --
Gastrointestinal 182 (3.0) 120 (1.99) 1.50 (1.19-1.89) <0.001 99
Life-threatening bleeding 175 (2.88) 212 (3.52) 0.81 (0.66-0.99) 0.04 156
Major bleeding 375 (6.17) 397 (6.59) 0.93 (0.81-1.07) 0.31 --
Minor bleeding 1787 (29.4) 1931 (32.0) 0.91 (0.85- 0.967) 0.005 38
Major bleeding: hemoglobin reduction 20 gm/liter, transfusion 2 units blood, symptomatic bleeding in a
critical area or organ; life-threatening bleeding: fatal bleeding, symptomatic intracranial bleeding, bleeding
with a decrease in hemoglobin 50 gm/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); NNH: number
needed to harm
ii. Apixaban13
1. Statistically significant lower rates of major bleeding, intracranial
bleeding, and any bleeding in apixaban group compared to warfarin
2. No statistical difference between gastrointestinal bleeding rates in the
apixaban group compared to warfarin
Table 4: Bleeding Events in Apixaban Patients with Nonvalvular Atrial Fibrillation13
Apixaban 5 mg twice Warfarin Hazard Ratio P-value NNH
daily (n=9088) (%) (n=9052) (%) (95% CI)
Major Bleeding 327 (3.6) 462 (5.1) 0.69 (0.60-0.80) <0.001 66
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) <0.001 128
Any bleeding 2356 (25.9) 3060 (33.8) 0.71 (0.68-0.75) <0.001 12
Major bleeding: decrease in hemoglobin of 2 gm/dL or transfusion 2 units packed red cells, occurring in a
critical site or resulting in death
iii. Rivaroxaban14
1. No statistically significant difference between rivaroxaban and
enoxaparin/warfarin bleeding rates
Table 5: Bleeding Events in Rivaroxaban Patients in the Treatment of Symptomatic Venous
Thromboembolism14
Rivaroxaban Enoxaparin/warfarin Hazard Ratio P-value
(n=1731) (%) (n=1718) (%) (95% CI)
Major bleeding 14 (0.8) 20 (1.2) 0.65 0.21
(0.33-1.3)
Clinically relevant nonmajor bleeding 126 (7.3) 119 (7.0) -- --
First major or clinically relevant 139 (8.1) 138 (8.1) 0.97 0.77
nonmajor bleeding occurring during (0.76-1.22)
treatment
Major bleeding: decrease hemoglobin 2 gm/dL and/or transfusion 2 units blood or both, bleeding in a critical
site, contributing to death

Hinds 4
III. Clinical question
A. Given the risk of bleeding with new oral anticoagulants, how can they be
reversed?
IV. Reversal of new oral anticoagulants
A. Reversal strategies in prescribing information
i. Apixaban8
1. No established reversal
2. Effects lasting at least 24 hours after last dose
3. Use of prothrombin complex concentrate (PCC), activated prothrombin
complex concentrate (aPCC), or recombinant factor VIIa (rFVIIa) may be
considered (no evaluation in clinical studies)
4. Activated charcoal reduces absorption of apixaban
ii. Dabigatran7
1. No specific reversal agent
2. Hemodialysis removes dabigatran but limited clinical experience in use
3. Use of aPCCs, rFVIIa, or concentrates of coagulation factors II, IX, or X
may be considered (no clinical trial data)
4. If bleeding complications occur, stop dabigatran, provide clinical
support, and look for source of bleeding
iii. Rivaroxaban9
1. No specific antidote
2. Partial reversal of prothrombin time prolongation with PCC
administration in healthy volunteers
3. Use of aPCC or rFVIIa not evaluated
4. Consider activated charcoal in overdose
B. Supportive measures15,16,17
i. Observation and withdrawal of further anticoagulant therapy
ii. Activated charcoal if <2 hours since administration of NOAC
iii. Hemodialysis
1. Dabigatran only (least protein bound agent)
2. Removes ~60% of the drug (48.8%-68% at 4 hours)
iv. Mechanical compression
C. Reversal strategies
i. Fresh frozen plasma (FFP)18
1. Plasma transfusion
2. Contains coagulation factors in normal serum concentrations
a. Significantly less coagulation factors when compared to PCCs
3. Mechanism of action: restores all coagulation factors
4. Limitations: must be thawed, ABO matching required, large volume of
administration
a. Dose: 10-15 mL/kg
5. Adverse effects: fluid overload, infectious disease, transfusion related
acute lung injury, allergic reactions, risk of thromboembolism
6. Reduced intracranial hemorrhage volume in a mouse model after
administration of dabigatran
ii. 3-factor prothrombin complex concentrates (3F-PCC)16,17
1. Similar concentrations of nonactivated factors II, IX, and X but low
concentrations of nonactivated factor VII
a. Some formulations may contain additional agents/proteins

Hinds 5
 2. Proposed mechanism of NOAC reversal: large amounts of factor X may
decrease inhibitory effects of factor Xa inhibitors; may overcome factor
Xa inhibition by increasing thrombin generation20
3. Only 2 available in the US (Bebulin VH and Profilnine SD)
4. 3F-PCC less likely to increase thrombosis than 4F-PCC
a. 0.7% reported incidence of thromboembolic events with 3F-PCC
versus 1.8% in 4F-PCC in reversal of warfarin21
5. Warning: risk of transmitting infectious agents is possible
6. Bebulin VH: factor IX complex nanofiltered and vapor heated21
a. Indication: control/prevention of bleeding episodes in adults
with hemophilia B (congenital factor IX deficiency)
b. Contains factor II, IX, X, low amounts of factor VII and heparin
c. Contraindications: allergy to heparin, history of HIT (heparin
induced thrombocytopenia)
d. Adverse effects: hypotension, dizziness, urticaria, erythema,
pyrexia, chills, DVT, PE, stroke, disseminated intravascular
coagulation (DIC)
7. Profilnine SD: factor IX complex solvent detergent treated22
a. Indication: control and prevention of bleeding in factor IX
deficient patients due to hemophilia B
b. Contains factor II, IX, X, and low levels factor VII
c. Adverse effects: urticaria, nausea, vomiting, headache, fever,
chills, somnolence, thrombosis, DIC
i. Infrequent but consistent reports have been described
which indicate that patients are at greater risk of
developing thrombosis22
iii. 4-factor prothrombin complex concentrates (4F-PCC)16
1. Similar concentrations of factors II, VII, IX, and X
a. Contains higher concentrations of factor VII compared to 3F-
PCCs
b. Some formulations contain additional coagulants
c. Available in activated and nonactivated factor VII
2. Warning: risk of transmitting infectious agents is possible
3. Kcentra16,23
a. Non-activated 4F-PCC contains 25 times more concentrated
coagulation factors than found in the plasma
b. Indication: urgent reversal of acquired coagulation factor
deficiency induced by vitamin K antagonist in acute major
bleeding or need for urgent surgery/invasive procedure
c. Contains factors II, VII, IX, X, proteins C and S, antithrombin III
d. Dose: based on INR values and weight
e. Mechanism of action: rapidly increases plasma levels of vitamin
K-dependent coagulation factor II, VII, IX, and X and proteins C/S
f. Contraindicated: DIC, HIT
g. Adverse effects:
i. Most frequent: headache, nausea, hypotension, anemia
ii. Most severe: stroke, PE, DVT, increased risk of
thrombosis
iii. Thromboembolic events in acute major bleeding study
(8.7%): stroke (1.9%), venous calf thrombosis (1%), DVT
(1%), fistula clot (1%)

Hinds 6
 4. FEIBA24
a. Activated 4F-PCC
b. Indication: treatment of spontaneous bleeding episodes or
surgical interventions in hemophilia A and B patients
c. Contains factors II, IX, X, and activated factor VII
d. Mechanism of action: rapidly increases plasma levels of vitamin
K-dependent coagulation factors II, VII, IX, and X (see Appendix
B, pg 19)
e. Contraindicated: normal coagulation mechanism, treatment of
bleeding episodes resulting from coagulation factor deficiencies
in the absence of inhibitors to coagulation Factor VIII or IX, DIC,
acute thrombosis or embolism
f. Adverse effects: thrombosis, somnolence, dizziness, nausea,
pyrexia, chills, bleeding in nonhemophiliac patients
i. Rate of thrombosis: 4-9 per 100,000 infusions25
1. Dose dependent side effect
iv. Recombinant factor VIIa (rFVIIa)
1. NovoSeven16,26
a. Indication: Peri-operative management and treatment of
bleeding episodes in adults/children with hemophilia A or B
with inhibitors; congenital factor VII deficiency or acquired
hemophilia; Glanzmanns thrombasthenia with refractoriness to
platelet transfusions
b. Contains activated factor VII
c. Mechanism of action: after complexing with tissue factor (TF),
activated coagulation factor X to factor Xa and factor IX to factor
IXa; factor Xa then converts prothrombin to thrombin and forms
a hemostatic plug via the conversion of fibrinogen to fibrin
d. Adverse effects: thrombosis, bleeding
i. Black box warning: can cause arterial and venous
thrombotic events
ii. 4% occurrence of thromboembolic events (cerebral
artery occlusion, cerebral ischemia, angina pectoris,
myocardial infarction, PE, DVT)
Table 6: PCCs available in the US21,22,23,24,25,26
Brand Components Dose Time Duration Cost
Names to (hr) (AWP)
effect
(min)
3F-PCCs Bebulin VH Factors II, IX, X, low 25-70 units/kg 10 6-8 $1.14/
concentration factor IU
VII, heparin
Profilnine Factors II, IX, X, low 1 unit/kg will 10 6-8 $1.19/
SD concentration factor VII increase Factor IX 1% IU
Activated FEIBA NF Factors II, VII, IX, X, 50-100 units/kg 15 8-12 $2.17/
4F- PCC IU
4F-PCC Kcentra Factors II, VII, IX, X, 25-50 units/kg 15 6-8 $2.17/
protein C/S, IU
antithrombin III
rFVIIa NovoSeven Activated rFVIIa 15-90 mcg/kg 10 <1 $1.64/
mcg
AWP: average wholesale price

Hinds 7
 Table 7: PCC Components (units/mL) 21,22,23,24,26
Bebulin VH Profilnine SD FEIBA NF Kcentra*
Factor II 24-38 35-40 1.3 units/FEIBA unit 19-40

Factor VII <5 10 0.9 units/FEIBA unit 10-25

Factor IX 24-38 25 1.4 units/FEIBA unit 20-31

Factor X 24-38 25 1.1 units/FEIBA unit 25-51

Heparin <0.15 U/U Factor IX -- -- 0.4-2

*Kcentra also contains proteins C/S and antithrombin III; heparin theorized to decrease risk of thrombosis
D. Drugs on the horizon
i. Andexanet alfa (r-antidote)27
1. Catalytically inactive, recombinant protein, binds to direct factor Xa
inhibitors and activated antithrombin III
a. Dose dependently reverses the inhibition of factor Xa inhibitors
2. Phase 1 trial, 32 healthy volunteers randomized to receive various single
IV bolus doses of andexanet alfa (30, 90, 300, or 600 mg) or placebo28
a. Rivaroxaban added to plasma samples ex vivo
b. Anticoagulant effect reversed in a dose-dependent fashion
c. No thrombotic events/deaths reported over 28 day follow up25
3. Currently in phase 2 and 3 trials29,30
a. Serious reported adverse effects: 1 case of pneumonia
b. Administration of andexanet alfa IV bolus followed by a 2 hour
continuous infusion after the administration of apixaban
produced a rapid, nearly complete, and sustained reversal of the
anticoagulant effect
c. Ongoing phase 2 proof-of-concept study interim results for 6 day
treatment with apixaban 5 mg twice daily (n=6), after a 420 mg
bolus andexanet alfa; anticoagulant reversal of apixaban was
92% (p<0.0001) compared to placebo (n=3), and after the two
hour infusion, reversal was 91% (p<0.0001)
d. 210 mg and 420 mg of andexanet alfa reversed rivaroxabans
anticoagulant effects (20 mg daily) by 32% and 51% after 2
minutes, respectively
ii. PER97731
1. Synthetic small molecule antidote for potential reversal of apixaban,
rivaroxaban, dabigatran, fondaparinux, low molecular weight heparin
2. Demonstrated ex vivo reversal of apixaban and rivaroxaban when
analyzing aPTT and anti-Xa levels
iii. aDabi-Fab32
1. Antibody fragment for reversal of dabigatran
2. Mimics thrombin, high affinity for dabigatran
3. Reversed dabigatran clotting time in an in vivo rat model

Hinds 8
V. Evidence for Reversal of New Oral Anticoagulant
Table 8: Perzborn E, Heitmeier S, Laux V, Buchmuller A. Reversal of rivaroxaban-induced
anticoagulation with prothrombin complex concentrate, activated prothrombin complex concentrate
and recombinant activated factor VII in vitro. Thromb Res. 2014;133:671-681.33
Purpose To determine the potential of PCC, aPCC, and rFVIIa to reverse the anticoagulant activity of
rivaroxaban in human blood
Design In vitro study
Inclusion Healthy subjects
Exclusion Medications in previous 10 days
Outcomes Reversal of anticoagulant effects by measuring prothrombin time (PT), clotting time (CT),
thrombin generation (TG), lag time, maximum concentration of TG (Cmax), endogenous
thrombin potential (ETP) (see Appendix D, pg. 20)
Methods Rivaroxaban was diluted to a concentration to simulate a 20 mg dose and hypothetical
overdoses and added to blood samples from healthy subjects; test conducted for 1 hour
Reversal agents were also diluted to simulate reasonable human plasma concentrations
aPCC (FIEBA) 0.2 U/mL, 0.4 U/mL, 0.7 U/mL (50 U/kg), 1 U/mL (50-100 U/kg)
4F-PCC (Beriplex) 0.4 U/mL (25 U/kg), 0.2 U/mL, 0.7 U/mL (50 U/kg) (comparable to
Kcentra factor concentrations)
rFVIIa (Novoseven) 5 g/mL (270 g/kg), 15 g/mL, 50 g/mL
Statistics Analysis of variance (ANOVA) and Tukeys multiple comparison test
Results Rivaroxaban 200-1000 ng/mL prolonged PT in human plasma by 2.1 to 5.5 fold from baseline
in a concentration dependent fashion
Prothrombin time (PT)
PCC: decreased PT by 15-22% from 13.1 seconds to 12.3 seconds (not significant at 200
ng/mL, n=7); reversal significant at 500 ng/mL and 1000 ng/mL (P<0.001 vs
rivaroxaban)
aPCC: significantly shortened PT by 22-24% from 12.8 seconds to 9.2 seconds
(concentration dependent, P<0.001 vs. rivaroxaban, n=5); ceiling effect at 0.7 U/mL in all
rivaroxaban concentrations
rFVIIa: 5-50 g/mL significantly shortened PT from 12.9 seconds to minimum of 7.3
seconds (P<0.001 vs rivaroxaban, n=7); all rFVIIa concentrations significantly reversed
rivaroxaban induced PT prolongation by 47-54% (dose dependent)
PT Reversal effect rFVIIa>aPCC>PCC
Clotting time (CT)
PCC: did not affect CT (n=2-3)
aPCC: reversed CT by 24-40% but only statistically significant at 1656 ng/mL
rivaroxaban (P<0.001 vs. rivaroxaban, n=5)
rFVIIA: reduced CT prolongation by 37-53%; significant at 1807 ng/mL rivaroxaban
(P<0.001 vs. rivaroxaban, n=4)
Lag time
PCC: slightly reversed lag time, significant in 1000 ng/mL rivaroxaban at 0.2 U/mL
(P<0.001 vs rivaroxaban, n=7) and at higher concentrations of PCC in 500 ng/mL
rivaroxaban
aPCC: significantly reversed lag time for all aPCC and rivaroxaban concentrations
(P<0.001 vs rivaroxaban, n=5)
rFVIIa: significantly reversed lag time for all aPCC and rivaroxaban concentrations
(P<0.001 vs rivaroxabn, n=6-8)
Lag time reversal: rFVIIa>aPCC>PCC
Endogenous thrombin potential (ETP)
PCC: significantly reversed rivaroxaban 200 ng/mL at 0.2 U/mL (P<0.01 vs rivaroxaban);
increased above baseline at higher PCC concentrations (n=7); slightly increased ETP at
higher rivaroxaban concentrations
aPCC: significantly increased ETP above baseline in 200 ng/mL rivaroxaban and
significantly reversed rivaroxaban 500 ng/mL at 0.4 U/mL (P<0.01 vs rivaroxaban, n=5);
slight increase of ETP in rivaroxaban 1000 ng/mL at 0.4 U/mL and above (P<0.01 vs.
rivaroxaban)
Hinds 9
 Table 8 (Continued): Perzborn E, Heitmeier S, Laux V, Buchmuller A.33
Results rFVIIa: no significant reversal effect (n=7)
(Continued) Maximum concentration of thrombin generation (Cmax)
PCC: no significant reversal of rivaroxaban (n=7)
aPCC: significant reversal of rivaroxaban 200 ng/mL for doses above 0.2 U/mL aPCC
(P<0.05 vs rivaroxaban) and rivaroxaban 500 ng/mL at 1 U/mL aPCC (P< 0.05 vs
rivaroxaban, n=5)
rFVIIa: significantly increased Cmax of rivaroxaban 200 ng/mL for all doses of rFVIIa;
significantly increased Cmax of rivaroxaban 500 ng/mL at doses above 5 g/mL rFVIIa
(P<0.01 vs. rivaroxaban) and rivaroxaban 1000 ng/mL at 50 g/mL rFVIIa (P<0.01 vs
rivaroxaban, n=6-8)
aPCC and rFVIIa partially reversed inhibition of Cmax
Authors All agents were partially effective for reversal of rivaroxaban-induced anticoagulation
Conclusions rFVIIa and aPCC were more effective than PCC in reversal of PT, CT, lag time of TG
Comments Strengths
Compared multiple reversal agents at different doses
Simulated therapeutic and overdose concentrations of rivaroxaban
Limitations
Clot based assays may not predict reversal potential of agents
In vitro study
Agent availability and application in the U.S.

Table 9: Escolar G, Fernandez-Gallego, Arellano-Rodrigo E, et al. Reversal of apixaban induced

alterations in hemostasis by different coagulation factor concentrates: significance of studies in vitro
with circulating human blood. Plos ONE. 2013;8(11):e78696.34
Purpose To investigate the effects of apixaban on platelets and hemostasis in humans and determine
the effectiveness of different factor concentrations at reversing apixabans effects on
hemostasis
Design In vitro study design
Inclusion Healthy volunteers
Exclusion Patients using acetylsalicylic acid, non-steroidal anti-inflammatory or antiplatelet drugs
within the past 7 days
Outcomes Clotting assays, measure TG, clot formation time (CFT) and maximum clot firmness (MCF) as
well as thrombin peak, lag phase, and time peak to determine reversal of apixaban and
determine effects in damaged vasculature (see Appendix D, pg 20)
Methods Blood samples were donated and apixaban was added to the samples at a concentration
of 200 ng/mL, twice the average Cmax achieved in patients receiving dosages for atrial
fibrillation
The following coagulation factor concentrates were tested on apixaban:
o rFVIIa (Novoseven) 270 g/kg
o aPCC (FEIBA) 75 U/kg
o 4F-PCC (Beriplex) 50 IU/kg (similar to 4F-PCC Kcentra)
Assumed a patients weight was ~70kg
Used whole blood samples to analyze clot formation for 45 minutes
Coagulation factor concentrates were tested in blood samples and reversal of
anticoagulant effect was analyzed via clotting assays
Blood was perfused through rabbit aortas to analyze changes when exposed to damaged
vascular components
Statistics ANOVA and Wilcoxon-Mann-Whitney test for Gaussian distribution

Hinds 10
 Table 9 (Continued): Escolar G, Fernandez-Gallego, Arellano-Rodrigo E, et al.34
Results N=12, ages 22-42 years
Table 9a: Thrombin Generation Initiated in Plasma with Phospholipids
and Tissue Factor
RCL Lag Thrombin Time CT (s) CFT (s) MCF
reagent phase peak (nM) peak (mm)
(min) (min)
CON 15.5 349.730 24.2 165.6 262.939.4 532.2
2.3 4.1 19.7
Apix 34.3 75.823* 42.2 357.9 923.8 40.27.7
5.5* 8.9 52.8* 353.9
Apix+ 15.4 159.8 34.2 95.1 140.1 62.3
rFVIIa 1.9** 41.1# 6.6 15.9** 33.9# 2.1#
Apix+ 14.2 221.1 37.15 102 116.1 62.7
aPCC 1.1** 50.1# 9.8** 12.5# 0.8#
Apix+ 25.0 169.47 42.8 326 430.7 56.9
PCC 4.5 8.7 86.3 117.6 1.6#
*P<0.01 vs control; **P<0.01 vs apixaban; #P<0.05 vs apixaban; CON:control;
Apix:apixaban
rFVIIa and aPCC significantly normalized the prolongation to reach peak TG
rFVIIa and aPCC significantly reversed lag phase and thrombin peak
rFVIIa and aPCCs significantly reduced prolongation of CT and CFT
Apixaban: apixaban reduced fibrin formation/platelet interaction in damaged vessels
o aPCCs, PCCs, and rFVIIa returned fibrin levels to baseline
rFVIIa partially reversed apixabans effects on platelet interactions
Authors aPCC shows a potential for apixaban reversal
Conclusions aPCC may be a first line reversal agent for apixaban
Do not recommend rFVIIa due to thrombogenicity, especially with off label use
Results may vary based on specific assays
Comments Strengths
Examined apixaban concentrations with twice the average Cmax in patients on therapeutic
doses of apixaban
Limitations
In vitro design limits applicability of study conclusions
Short time period for collecting data and availability of agents
Rabbit aorta used to study damaged tissue may lead to different conclusions

Table 10: Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific
reversal agent on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemostasis.
2012;108:217-224.35
Purpose To determine the potential of PCC, aPCC, and rFVIIa to reverse the anticoagulant activity of
dabigatran and rivaroxaban in human blood
Design Randomized, placebo-controlled, crossover, ex-vivo design
Inclusion Healthy males, ages 18-45, BMI 18-30 kg/m2
Exclusion Personal or family history of thrombosis or bleeding disorders, renal or liver impairment
Outcomes Clotting assays, measure ETP, thrombin peak, lag time, time to reach maximum peak (see
Appendix D, pg 20)
Methods Randomized participants received one dose of dabigatran 150 mg or rivaroxban 20 mg
15 day washout period between crossover doses
Blood samples collected before then 2 hours after drug administration
Reversal agents tested
o 4F-PCC (Kanokad) 0.25 U/mL, 0.5 U/mL (25 IU/kg), 1 U/mL (similar to Kcentra)
o aPCC (FEIBA) 0.25 U/mL, 0.5 U/mL, 1 U/mL (80 IU/kg), 2 U/mL
o rFVIIa (Novoseven) 0.5 g/mL, 1.5 g/mL, 3 g/mL ( 120 g/kg)
Hinds 11
 Table 10 (Continued): Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G.35
Statistics Paired t-test, Shapiro-Wilks test, Wilcoxon signed-ranks test for normality;
Spearmans coefficient of rank correlation for correlation between parameters of TG
Results N=10
Rivaroxaban
ETP
PCC: dose dependent increase in ETP (37% with 0.25 U/mL PCC); only dose that reversed
ETP to near baseline; overcorrection by higher concentrations
aPCC: dose dependent increase in ETP (50% increase for 0.25 U/mL p<0.001, only dose
that reversed it to near baseline); overcorrection by higher concentrations
rFVIIa: no correction of ETP
Thrombin peak
PCC: dose dependent correction
aPCC: dose dependent correction; 1 and 2 U/mL corrected peak close to baseline
(P=0.02)
rFVIIa: reduced peak (P=0.02)
Lag time
PCC: small reduction in lag time (15%)
aPCC: significant reduction (47%, P<0.0001, rate of thrombin increased to >25 nM/min
but did not reach baseline rate)
rFVIIa: complete reversal of lag time to baseline (P<0.001, rate of thrombin increased to
>25 nM/min but did not reach baseline rate)
Time to reach maximum concentration of thrombin
PCC: no effect
aPCC: decreased time to peak concentration by 30% (p<0.001); increased rate of
thrombin formation but did not reach baseline
rFVIIa: decreased time to peak concentration by 44% (P<0.001); increased rate of
thrombin formation but did not reach baseline
Dabigatran
ETP
PCC: dose dependent increase in ETP; reached baseline at lowest dose (P=0.02)
aPCC: dose dependent increase in ETP; reached baseline at lowest dose (P=0.02)
rFVIIa: no correction of ETP
Thrombin peak
PCC: increased thrombin peak above baseline at lowest dose (P<0.001)
aPCC: increased thrombin peak above baseline at lowest dose (P<0.001)
rFVIIa: did not increase thrombin peak above baseline
Lag time
PCC: no significant correction of lag time
aPCC: all doses except 0.25 U/mL reduced lag time (P<0.001)
rFVIIa: highest dose significantly decreased lag time (P<0.001)
Time to reach maximum concentration of thrombin
PCC: no effect
aPCC: significantly reduced by lowest dose of aPCC (P=0.03) close to baseline
rFVIIa: reduced time to reach maximum concentration
Authors aPCC combines the reversal effects of PCC and rFVIIa to correct both lag time and peak
Conclusions aPCC is the most reasonable theoretical option for reversal of rivaroxaban
Animal models do not provide evidence for use of rFVIIa
aPCC may be useful for dabigatran dosing, but the dose needs to be determined
Comments Strengths
Randomized, placebo controlled trial
Limitations
Ex vivo study design limits applicability of study conclusions
Duration or response not assessed (short half-lives of reversal agents)
Assessed one dose of anticoagulant; availability of agent; no active bleeding

Hinds 12
 Table 11: Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of
rivaroxaban and dabigatran by prothrombin complex concentrate. Circ. 2011;124:1573-1579.18
Purpose To determine if PCC would reverse the anticoagulant effects of rivaroxaban and dabigatran
Design Randomized, double-blind, placebo-controlled, crossover study (blinded to placebo/PCC)
Background PCC (Cofact): non-activated 4F-PCC (factors II, VII, IX, X, proteins C and S, antithrombin);
similar concentration to Kcentra
Inclusion Healthy male individuals (normal blood count, kidney, and liver function, negative for
Hepatitis B and C and HIV)
Outcomes Rivaroxaban: PT and ETP (see Appendix D, pg. 20);
Dabigatran: activated partial thromboplastin time (aPTT), ETP, lag time, thrombin time (TT),
ecarin clotting time (ECT) (see Appendix D, pg. 20)
Methods Received dabigatran (150 mg BID) or rivaroxaban (20 mg BID) for 2.5 days
Received either PCC infusion (Cofact) 50 IU/kg or saline on day 3, and monitored blood
for 24 hours
11 day washout period
Blood collected at baseline, day 3, 15 and 30 minutes, then 1, 2, 4, 6, and 24 hours after
infusion
Statistics Paired t-test and repeated measures using ANOVA for confirmation;
Between group comparison used the independent-sample t test
Results N=12, Age: 24 4 years, BMI: 23 3 kg/m2
Table 11a: Eerenberg Results
Parameter Baseline Rivaroxaban Dabigatran
Pre-PCC Post-PCC Pre-PCC Post-PCC
PT (sec) 12.30.7 15.81.3 12.81.0 -- --
(P<0.001) (P<0.001)
ETP (%) 9222 5121 11426 -- --
(P=0.002) (P<0.001)
aPTT (sec) 33.63.3 -- -- 59.415.8 70.310.3
(P<0.001) (P=0.64)
ETP lag 2.90.4 -- -- 7.52.5 8.72.6
time (min) (P<0.001) (P=0.20)
ECT (sec) 331 -- -- 6926 86 20
(P=0.002) (P=0.08)
Studied effects persisted until the last measurement at 24 hours unless specified below
TT prolongation remained immeasurable for at least 6 hours after PCC infusion
4F-PCC significantly increased ETP (amount of thrombin generated) in rivaroxaban
samples and significantly reversed PT prolongation
4F-PCC did not significantly reverse aPTT, ETP, or ECT in dabigatran samples
Saline did not significantly affect results after the anticoagulant was administered
Adverse effects: small hematoma at infusion site occurred in 2 rivaroxaban and 2
apixaban patients, gingival bleeding in 2 dabigatran patients
Authors Nonactivated 4F-PCC reversed the effect (PT, ETP) of full-dose rivaroxaban immediately
Conclusions but did not reverse dabigatran at the dose studied
No support to use nonactivated 4F-PCC for reversal of direct thrombin inhibitors
Comments Strengths
Randomized, double-blind, placebo controlled trial
Anticoagulants and 4F-PCC administered to participants
Limitations
Participants received financial compensation
All male participants
Rivaroxaban dose higher than normal treatment dose
Accuracy of coagulation tests in monitoring reversal potential of 4F-PCC
No active bleeding to assess actual reversal
Used only one dose of one PCC agent; availability of agent

Hinds 13
 A. Levi et al conducted a trial examining the reversal of rivaroxaban using 3F-PCC
(Profilnine SD) and 4F-PCC (Beriplex)35
i. Randomized, open-label single center, parallel group study, n=35
1. Inclusion criteria: healthy, 18-55 years old, normal creatinine clearance,
BMI 18-30 kg/m2, not pregnant, normal coagulation tests at baseline
2. Exclusion criteria: history of thrombosis, thrombophilia/bleeding
tendency/coagulopathy
ii. Methods: Received rivaroxaban 20 mg twice daily for 4.5 days, then given one
dose of either 50 IU/kg 3F-PCC (n=12), 50 IU/kg 4F-PCC (n=10), or saline bolus
(n=12) 4 hours after the last rivaroxaban dose
1. Blood samples collected pre-dose daily and up to 28 hours after last
rivaroxaban dose
iii. Outcomes: PT, thrombin generation assay, aPTT, anti Xa level
Table 12: Levi et al Reversal Results of 3F-PCC and 4F-PCC on Rivaroxaban36
Rivaroxaban 3F-PCC 4F-PCC
ETP Decreased Increased faster than 4F-PCC to Increased above pre-study
above pre-study levels levels
Lag time Prolonged (2-3 min) No effect No effect
PT Prolonged (21 sec) Reduced (20sec)* Reduced (17.5 sec)*
Thrombin Decreased Increased Increased < 3F-PCC
level (slow response initially)
Time to peak Prolonged Decreased Decreased < 3F-PCC
aPTT Prolonged (8 sec) Prolonged then return to Prolonged then return to
baseline (4 sec) baseline (6 sec)
Anti-Xa Increased No effect No effect
*30 minutes after PCC administration
iv. Adverse effects: 18 patients (51.4%)
1. 15 reported during rivaroxaban monotherapy, 2 in 3F-PCC, 2 in 4F-PCC
2. Most common adverse effects: abdominal discomfort, gingival bleeding,
back pain, headache (8.6% for each category)
a. Gingival bleeding (n=3), mouth hemorrhage (n=1)
b. No thromboembolic events reported
v. Conclusion: 4F-PCC and 3F-PCC partially reverse anticoagulant effects of
rivaroxaban and appear safe and well tolerated
1. 3F-PCC and 4F-PCC had different intensity of reversal on PT and
thrombin generation
VI. Summary of evidence for reversal of new oral anticoagulants
A. Human studies
i. Apixaban
1. aPCCs and rFVIIa partially reverse its anticoagulant parameters34
2. 4F-PCCs did not reverse anticoagulant parameters
ii. Dabigatran
1. 4F-PCC reversal of dabigatan conflicting
a. Activated 4F-PCC reversed peak thrombin and lag time34
b. Non-activated 4F-PCC did not reverse aPTT, ETP ECT32
2. rFVIIa reverses lag time
iii. Rivaroxaban
1. aPCC and rFVIIa are more effective than 4F-PCC for reversal of effects33
2. 4F-PCC partially reverses rivaroxaban

Hinds 14
 B. Murine Studies (see Appendix C, pg 20)37
i. Dabigatran
1. aPCC decreased mortality while rFVIIa did not
2. rFVIIa may have less reversal of hemostasis compared to aPCC
C. Rabbit (see Appendix C, pg 20)37
i. Apixaban
1. rFVIIa reduced bleeding time and PCC did not
ii. Dabigatran
1. aPCC decreased blood loss
iii. Rivaroxaban
1. rFVIIa and PCC reduced bleeding time but not blood loss
VII. Recommendations for the reversal of new oral anticoagulants
A. Recommendations for reversal of NOACs
i. Consider additional reversal methods of NOACs in severe bleeding defined as a
decrease in Hb 2 g/dL and/or transfusion of 2 units of whole blood
1. Apixaban
a. Consider administration of aPCC in healthy adults
b. If not on formulary, 4F-PCC may be considered
2. Dabigatran
a. Consider administration of aPCC in healthy adults
b. If all supportive measures fail (including hemodialysis), may
consider administration of aPCC in healthy adults
c. If aPCC not on forumulary, 4F-PCC may be considered
3. Rivaroxaban
a. Consider administration of aPCC in healthy adults
b. If not on formulary, 4F-PCC may be considered
ii. Use of these agents can increase risk of thrombosis
iii. Appropriate stratification and consent of patient is warranted prior to use of 4F-
PCCs
1. Only use if bleeding is severe and immediate action is required
2. Evidence supporting a specific dose is lacking
3. Limit repeat doses due to thrombosis risk
4. If bleeding not severe, wait for systemic drug concentration to decrease
since agents have short half-life
iv. Randomized controlled trials needed to determine most appropriate reversal
strategies and dose in the setting of acute bleeding, overdoses, comborbid
conditions, and renal impairment
1. Studies needed to determine if reversal of anticoagulant monitoring
parameters by PCCs/clotting factors correlates with reversal of bleeding
v. New drugs on the horizon
1. Established reversal agents coming soon

Hinds 15
References
1. 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
September 20, 2014.
2. Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-69.
3. Centers for Disease Control and Prevention. Atrial Fibrillation fact sheet. http://c.ymcdn.com/sites/
www.kphanet.org/resource/resmgr/KnowYourPharmacistResources/Fact_Sheet_atrial_fibrillati.pdf.
Updated 2010. Accessed September 20, 2014.
4. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation. CHEST. 2012;141(2
suppl):e531S-e575S.
5. 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.
6. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients.
CHEST. 2012;141(2 suppl):e278S-e325S.
7. Pradaxa (dabigatran) [package insert]. Ridgefield, CT; Boehringer-ingelheim; Revised September,
2014. https://www.pradaxa.com. Accessed September 20, 2014.
8. Eliquis (apixaban) [package insert]. Princeton, NJ; Bristol-Meyers Squibb; Revised August, 2012.
http://packageinserts.bms.com/pi/pi_eliquis.pdf. Accessed September 20, 2014.
9. Xarelto (rivaroxaban) [package insert]. Titusville, NJ; Jansenn; Revised September, 2014.
http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf. Accessed September 20, 2014.
10. Paikin JS, Eikelboom JW, Cairns JA, Hirsch C. New antithrombotic agents-insights from clinical trials.
Nat Rev Cardiol. 2010;7:498-509.
11. Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Prac Res Clin
Haematol. 2013;26:191-202.
12. Connolly SJ, Ezekowitz MD, Phil BD, et al. Dabigatran versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2009;363:1139-1151.
13. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2011;365:981-992.
14. The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J
Med. 2010;363:2499-2510.
15. Gonsalves WI, Pruthi RK, Patnaik MM. The new oral anticoagulants in clinical practice. Mayo Clin.
2013;88(5):495-511.
16. Ebright J, Mousa SA. Oral anticoagulants and status of antidotes for the reversal of bleeding risk
[published online ahead of print August 12 2014] . Clin Appl Thromb Hemost. 2014; http://
www.ncbi.nlm.nih.gov/ pubmed/25115762. Accessed September 20, 2014.
17. Babilonia K, Trujillo T. The role of prothrombin complex concentrates in reversal of target specific
anticoagulants. Thromb J. 2014;12:8.
18. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban
and dabigatran by prothrombin complex concentrate. Circ. 2011;124:1573-1579.
19. Kaatz S, Koides PA, Garcia DA, et al. Guidance on the emergent reversal of oral thrombin and factor Xa
inhibitors. Am J Hematol. 2012;87:S141-S145.
20. Dentali F, Marchesi C, Pierfranceschi MG, et al. Safety of prothrombin complex concentrates for rapid
anticoagulation reversal of vitamin K antagonists. Thromb Haemostasis. 2011;106(3):389-565.
21. Bebulin (Factor IX Complex), nanofiltered and vapor heated [package insert]. Westlake Village, CA;
Baxter; Revised July, 2012. https://www.baxter.com/downloads/healthcare_professionals/
products/bebulin_pi.pdf. Accessed September 20, 2014.
22. Profilnine SD-factor IV complex [package insert]. Los Angeles, CA; Grifols Biologicals; Revised August,
2010. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/
ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM261964.pdf. Accessed
September 20, 2014.
23. Kcentra prothrombin complex concentrate (human) [package insert]. Kankakee, IL; CSL Behring
GmbH; Revised December, 2013. http://www.kcentra.com/professional/
prescribing-information.aspx. Accessed September 20, 2014.
24. FEIBA NF (anti-inhibitor coagulant complex) [package insert]. Westlake Village, CA; Baxter
Healthcare Corporation; Revised February, 2011. http://www.feiba.com/us/forms/feiba_nf_pi.pdf.
Accessed September 20, 2014.
25. Awad NI, Cocchio C. Activated prothrombin complex concentrates for the reversal of anticoagulant-
associated coagulaopathy. P T. 2013;38:696-701.
Hinds 16
26. NovoSeven RT Coagulation Factor VIIa (recombinant) [package insert]. Bagsvaerd, Denmark; Novo
Nordisk; Revised July, 2014. http://www.novo-pi.com/novosevenrt.pdf. Accessed September 20,
2014.
27. Portola Pharmaceuticals. Portola pharmaceuticals announces first phase 2 results demonstrating
extended duration infusion with andexanet alfa (PRT4445). http://www.portola.com/clinical-
development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/. Updated 2014. Accessed September
25, 2014.
28. Cother MA, Kitt M, McClure M, et al. Randomized, double-blind, placebo-controlled single ascending
dose pharmacokinetic and pharmacodynamics study of PRT064445, a universal antidote for factor
Xa inhibitors (abstract). Arterioscler Thromb Vasc Biol. 2013;3:A10.
29. Lauw MN, Cppens M, Eikelboom JW. Recent advances in antidotes for direct oral anticoagulants: their
arrival is imminent. Can J Cardiol. 2014;30:381-384.
30. Crowther MA, Marthur V, Kitt M, et al. A phase 2 randomized, double-blind, placebo-controlled trial
demonstrating reversal of rivaroxaban-induced anticoagulation in healthy subjects by andexanet alfa
(PRT064445), an antidote for FXa inhibitors (abstract). Blood. 2013;122:A3636.
31. Laulicht B, Bakhru S, Lee C, et al. Abstract 11395: small molecule antidote for anticoagulants
(abstract). Circ. 2012;126:A11395.
32. Schneider G. An antidote on the horizon? An update on the progress toward achieving reversibility
for the new oral anticoagulants. Clinical Correlations. http://www.clinicalcorrelations.org/?p=7373.
Updated February, 2014. Accessed September 25, 2014.
33. Perzborn E, Heitmeier S, Laux V, Buchmuller A. Reversal of rivaroxaban-induced anticoagulation with
prothrombin complex concentrate, activated prothrombin complex concentrate and recombinant
activated factor VII in vitro. Thromb Res. 2014;133:671-681.
34. Escolar G, Fernandez-Gallego, Arellano-Rodrigo E, et al. Reversal of apixaban induced alterations in
hemostasis by different coagulation factor concentrates: significance of studies in vitro with
circulating human blood. Plos ONE. 2013;8(11):e78696.
35. Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G. Effect of non-specific reversal agent
on anticoagulant activity of dabigatran and rivaroxaban. Thromb Haemostasis. 2012;108:217-224.
36. Levi M, Moore KT, Castillejos CF, et al. Comparison of three-factor and four-factor prothrombin
complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy
volunteers. J Thromb Haemost. 2014;12(9):1428-1436.
37. Nutescu EA. Oral anticoagulant therapies: balancing the risks. Am J Health Syst Pharm. 2013;70;S3-
S11.
38. Baxter Healthcare Corportation. About FEIBA NF. http://www.feiba.com/us/HCP/hcp_aboutus.html.
Updated 2014. Accessed September 25, 2014.
39. Lee FM, Chan, AK, Lau kk, Chan HH. Reversal of new, factor-specific oral anticoagulants by rFVIIa,
prothrombin complex concentrate, and activated prothrombin complex concentrate: a review of
animal and human studies. Thromb Res. 2014;133:705-713.
40. Khoo TL, Weatherburn C, Kershawy G, Reddel CJ, Curnow J, Dunkley S. The use of FEIBA in the
correction of coagulation abnormalities induced by dabigatran. Int J Lab Hematol. 2013;35:222-224.

Hinds 17
Appendix A
7,8,9
Table 13: New Oral Anticoagulants Characteristics Table 14: Dabigatran Dosage
7
Dabigatran Apixaban Rivaroxaban Adjustments
Mechanism Reversibly Inhibits free Inhibits free Creatinine Dose
of action inhibits factor Xa and factor Xa and Clearance (CrCl)
thrombin clot-bound prothrombinase >30 mL/min 150 mg twice
(factor IIa) factor Xa and activity daily
prothrombinase
activity 15-30 mL/min 75 mg twice
daily
Side effects Bleeding Bleeding (1.1% Bleeding (1% in
(2.7%/yr in knee/hip major 30-50 mL/min + 75 mg twice
dabigatran vs. replacement) bleeding*) P-GP inh* daily
3.36%/yr nausea (2.6% in dyspepsia
warfarin for knee/hip (1.3% vs. 0.7% <30 mL/min + Avoid use
major replacement) placebo) P-GP inh
bleeding*) upper
<15 mL/min or No
gastrointestinal abdominal pain
dialysis recommendation
(35% vs. 24% (1.7% vs 0.2%
warfarin) placebo) *May decrease dosage to 75 mg twice
* Major bleeding: hemoglobin decreased by 20 gm/liter, transfusion daily with the following; P-GP inh:
9,11
2 units blood, symptomatic bleeding in a critical area/organ dronedarone or ketoconazole

8
Table 15: Apixaban Dosage Adjustments
Indication Dose Dosage Adjustment/Duration
Nonvalvular atrial fibrillation 5 mg twice daily 2.5 mg twice daily if at least 2: age 80, body
weight 60 kg, serum creatinine 1.5 mg/dL

DVT prophylaxis post hip/knee
replacement surgery and reduction
in risk of recurrent DVT/PE
Treatment of DVT
2.5 mg twice daily
10 mg twice daily, then
5 mg twice daily
Hip surgery: 35 days
Knee surgery: 12 days
DVT/PE: at least 6 months
10 mg x 7 days, 5 mg thereafter

Table 16: Rivaroxaban Dosage Adjustments
Indication
Nonvalvular atrial
fibrillation/reduce recurrence of
DVT/PE
Treatment of DVT/PE
Prophylaxis of DVT following hip or
knee replacement surgery
9
Dose Dosage Adjustment/Duration
20 mg daily CrCl 15-50 mL/min: 15 mg daily
CrCl<15 mL/min: avoid use
15 mg twice daily x 21 CrCl<30 mL/min: avoid use
days then 20 mg daily
10 mg daily CrCl<30 mL/min: avoid use
Hip surgery: 35 days duration
Knee surgery: 12 days duration

Hinds 18
Appendix B
Figure 2: aPCC (FEIBA) Mechanism of Action38

Appendix C
39,40
Table 17: Summary of NOAC Reversal Trials (human and non-human studies)
Author/ Model NOAC Reversal Conclusion
Date Agent
Zhou murine dabigatran 4F-PCC 4F-PCC decreased mortality to baseline, prevented
2011 rFVIIa growth of hematoma; rFVIIa did not
Lambourne murine dabigatran rFVIIa All failed to reduce blood loss; aPCC and rFVIIa+PCC
2012 PCC reduced bleeding time; rFVIIa may have less
rFVIIA+PCC hemostatic reversal potential relative to aPCC
aPCC
Zhou murine dabigatran Murine FFP All reversal agents significantly reduced hematoma
2013 Human expansion; rFVIIa reversed hematoma expansion
rFVIIa and improved neurological deficits
Perzborn rat rivaroxaban rFVIIa All reduced prolongation of bleeding time
2013 PCC
aPCC
Pragst rabbit dabigatran 4F-PCC Reduced blood loss and decreased time of
2012 hemostasis in a dose-dependent manner
Godier rabbit rivaroxaban rFVIIa Both significantly reduced bleeding time but not
2012 PCC reversal of blood loss
Godier rabbit apixaban rFVIIa Neither significantly decreased blood loss; rFVIIa
2013 (IV) PCC partially reduced bleeding time
Perzborn baboon rivaroxaban rFVIIa aPCC normalized bleeding time; rFVIIa partially
2013 PCC decreased bleeding time
aPCC
Khoo human dabigatran aPCC aPCC normalized peak thrombin generation/lag time
2013

Hinds 19
Appendix D
Table 18: Laboratory Assays for Assessment of NOACs35,37
Parameter Definition Application
Activated partial Time from the addition of Linear response to dabigatran up to therapeutic
thromboplastin time calcium to formation of a fibrin dose (not quantitative in overdose)
(aPTT) clot
Anti-Xa Measures the change in Monitoring factor Xa inhibitors (if calibration
absorbance of specific clotting and appropriate control agent available)
factor Xa activity
Clot formation time Speed of clot formation from 2 Prolonged by apixaban
(CFT) mm to 20 mm above baseline in
seconds
Clotting time (CT) Measures conversion of May be useful for dabigatran to steady-state
fibrinogen to fibrin (time until levels; increased by rivaroxaban and apixaban
clot reaches 2 mm)
Ecarin clotting time Measures thrombin generation Most useful test for monitoring dabigatran; dose
(ECT) (ecarin activates prothrombin) dependent increase when dabigatran present
Endogenous Area under the curve, maximum Decreased by rivaroxaban and dabigatran
thrombin potential amount of thrombin produced
(ETP)
Lag time (LT) Time to start thrombin Prolonged by dabigatran, rivaroxaban, apixaban
generation
Maximum clot Firmness of clot formed, strength Decreased by apixaban
firmness (CFT) of fibrin/platelet clot
Maximum Maximum concentration of Decreased by rivaroxaban
concentration of thrombin generated
thrombin (Cmax)
Prothrombin time Time for plasma to clot after Prolonged when dabigatran present (not as
(PT) calcium and thromboplastin extensive as aPTT response); more responsive to
added factor Xa inhibitors
Thrombin time (TT) Activity of thrombin in plasma Less applicable than ECT, increased when
dabigatran present (qualitative)
Time to peak Time to reach maximal effect of Prolonged by apixaban, rivaroxaban, dabigatran
thrombin generation
Other labs Complete blood count, Hemoglobin/hematocrit and platelets
serum creatinine (bleeding), creatinine clearance (renal function)
Coagulation assays and effect on patient outcomes not established; different reagents used in laboratory
settings have different responsiveness

Hinds 20