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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

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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 DVT/PE after initial therapy

X X

Stroke prevention in nonvalvular atrial fibrillation

X X X

DVT prophylaxis following replacement surgery of hip or knee

X X

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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

thrombin inhibitor) Factor Xa Factor Xa

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/

inhibitors P-gp inducers/ inhibitors, 3A4

P-gp inducers/ 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

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Table 3: Bleeding Events in Dabigatran vs Warfarin12 Dabigatran 150

mg twice daily (n=6076) (%)

Warfarin (n=6022) (%)

Relative Risk (95% CI)

P-value NNH

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

daily (n=9088) (%) Warfarin

(n=9052) (%) Hazard Ratio

(95% CI) P-value NNH

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 (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 nonmajor bleeding 126 (7.3) 119 (7.0) -- -- First major or clinically relevant

nonmajor 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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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

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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 thrombosis”22

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%)

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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; Glanzmann’s 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

Names Components Dose Time

to effect (min)

Duration (hr)

Cost (AWP)

3F-PCCs Bebulin VH Factors II, IX, X, low concentration factor

VII, heparin

25-70 units/kg 10 6-8 $1.14/ IU

Profilnine SD

Factors II, IX, X, low concentration factor VII

1 unit/kg will increase Factor IX 1%

10 6-8 $1.19/ IU

Activated 4F- PCC

FEIBA NF Factors II, VII, IX, X, 50-100 units/kg 15 8-12 $2.17/ IU

4F-PCC Kcentra Factors II, VII, IX, X, protein C/S,

antithrombin III

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

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

AWP: average wholesale price

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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 rivaroxaban’s 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

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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 μg/mL (270 μg/kg), 15 μg/mL, 50 μg/mL

Statistics Analysis of variance (ANOVA) and Tukey’s 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 μg/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)

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Table 8 (Continued): Perzborn E, Heitmeier S, Laux V, Buchmuller A.33

Results (Continued)

rFVIIa: no significant reversal effect (n=7) 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 μg/mL rFVIIa (P<0.01 vs. rivaroxaban) and rivaroxaban 1000 ng/mL at 50 μg/mL rFVIIa (P<0.01 vs rivaroxaban, n=6-8)

aPCC and rFVIIa partially reversed inhibition of Cmax Authors’ Conclusions

All agents were partially effective for reversal of rivaroxaban-induced anticoagulation 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 apixaban’s 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 μg/kg o aPCC (FEIBA) 75 U/kg o 4F-PCC (Beriplex) 50 IU/kg (similar to 4F-PCC Kcentra)

Assumed a patient’s 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

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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 reagent

Lag phase (min)

Thrombin peak (nM)

Time peak (min)

CT (s) CFT (s) MCF (mm)

CON 15.5± 2.3

349.7±30 24.2± 4.1

165.6± 19.7

262.9±39.4 53±2.2

Apix 34.3± 5.5*

75.8±23* 42.2± 8.9

357.9± 52.8*

923.8± 353.9

40.2±7.7

Apix+ rFVIIa

15.4± 1.9**

159.8± 41.1#

34.2± 6.6

95.1± 15.9**

140.1± 33.9#

62.3± 2.1#

Apix+ aPCC

14.2± 1.1**

221.1± 50.1#

37.1±5 102± 9.8**

116.1± 12.5#

62.7± 0.8#

Apix+ PCC

25.0± 4.5

169.4±7 42.8± 8.7

326± 86.3

430.7± 117.6

56.9± 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 apixaban’s effects on platelet interactions

Authors’ Conclusions

aPCC shows a potential for apixaban reversal 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 μg/mL, 1.5 μg/mL, 3 μg/mL ( 120 μg/kg)

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Table 10 (Continued): Marlu R, Hodaj E, Paris A, Albaladejo P, Crackowski JL, Pernod G.35

Statistics Paired t-test, Shapiro-Wilk’s test, Wilcoxon signed-ranks test for normality; Spearman’s 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’ Conclusions

aPCC combines the reversal effects of PCC and rFVIIa to correct both lag time and peak 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 13

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 Pre-PCC Post-PCC

Dabigatran Pre-PCC Post-PCC

PT (sec) 12.3±0.7 15.8±1.3 (P<0.001)

12.8±1.0 (P<0.001)

-- --

ETP (%) 92±22 51±21 (P=0.002)

114±26 (P<0.001)

-- --

aPTT (sec) 33.6±3.3 -- -- 59.4±15.8 (P<0.001)

70.3±10.3 (P=0.64)

ETP lag time (min)

2.9±0.4 -- -- 7.5±2.5 (P<0.001)

8.7±2.6 (P=0.20)

ECT (sec) 33±1 -- -- 69±26 (P=0.002)

86 ±20 (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’ Conclusions

Nonactivated 4F-PCC reversed the effect (PT, ETP) of full-dose rivaroxaban immediately 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 14

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 above pre-study levels

Increased above pre-study levels

Lag time Prolonged (2-3 min) No effect No effect

PT Prolonged (21 sec) Reduced (20sec)* Reduced (17.5 sec)*

Thrombin level

Decreased Increased (slow response initially)

Increased < 3F-PCC

Time to peak Prolonged Decreased Decreased < 3F-PCC

aPTT Prolonged (8 sec) Prolonged then return to baseline (4 sec)

Prolonged then return to 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 15

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 16

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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.

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Hinds 17

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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.

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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.

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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 18

Appendix A

Table 13: New Oral Anticoagulants Characteristics7,8,9

Dabigatran Apixaban Rivaroxaban

Mechanism of action

Reversibly inhibits

thrombin (factor IIa)

Inhibits free factor Xa and

clot-bound factor Xa and

prothrombinase activity

Inhibits free factor Xa and

prothrombinase activity

Side effects Bleeding (2.7%/yr

dabigatran vs. 3.36%/yr

warfarin for major

bleeding*)

gastrointestinal (35% vs. 24%

warfarin)

Bleeding (1.1% in knee/hip

replacement) nausea (2.6% in

knee/hip replacement)

Bleeding (1% in major

bleeding*) dyspepsia

(1.3% vs. 0.7% placebo)

upper abdominal pain (1.7% vs 0.2%

placebo)

* Major bleeding: hemoglobin decreased by 20 gm/liter, transfusion ≥ 2 units blood, symptomatic bleeding in a critical area/organ

9,11

Table 16: Rivaroxaban Dosage Adjustments9

Indication Dose Dosage Adjustment/Duration

Nonvalvular atrial fibrillation/reduce recurrence of

DVT/PE

20 mg daily CrCl 15-50 mL/min: 15 mg daily CrCl<15 mL/min: avoid use

Treatment of DVT/PE 15 mg twice daily x 21 days then 20 mg daily

CrCl<30 mL/min: avoid use

Prophylaxis of DVT following hip or knee replacement surgery

10 mg daily CrCl<30 mL/min: avoid use Hip surgery: 35 days duration

Knee surgery: 12 days duration

Table 14: Dabigatran Dosage Adjustments

7

Creatinine Clearance (CrCl)

Dose

>30 mL/min 150 mg twice daily

15-30 mL/min 75 mg twice daily

30-50 mL/min + P-GP inh*

75 mg twice daily

<30 mL/min + P-GP inh

Avoid use

<15 mL/min or dialysis

No recommendation

*May decrease dosage to 75 mg twice daily with the following; P-GP inh: dronedarone or ketoconazole

Table 15: Apixaban Dosage Adjustments8

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

2.5 mg twice daily Hip surgery: 35 days Knee surgery: 12 days

DVT/PE: at least 6 months

Treatment of DVT 10 mg twice daily, then 5 mg twice daily

10 mg x 7 days, 5 mg thereafter

Hinds 19

Appendix B

Figure 2: aPCC (FEIBA) Mechanism of Action38

Appendix C

Table 17: Summary of NOAC Reversal Trials (human and non-human studies)39,40

Author/ Date

Model NOAC Reversal Agent

Conclusion

Zhou 2011

murine dabigatran 4F-PCC rFVIIa

4F-PCC decreased mortality to baseline, prevented growth of hematoma; rFVIIa did not

Lambourne 2012

murine dabigatran rFVIIa PCC

rFVIIA+PCC aPCC

All failed to reduce blood loss; aPCC and rFVIIa+PCC reduced bleeding time; rFVIIa may have less

hemostatic reversal potential relative to aPCC

Zhou 2013

murine dabigatran Murine FFP Human rFVIIa

All reversal agents significantly reduced hematoma expansion; rFVIIa reversed hematoma expansion

and improved neurological deficits

Perzborn 2013

rat rivaroxaban rFVIIa PCC

aPCC

All reduced prolongation of bleeding time

Pragst 2012

rabbit dabigatran 4F-PCC Reduced blood loss and decreased time of hemostasis in a dose-dependent manner

Godier 2012

rabbit rivaroxaban rFVIIa PCC

Both significantly reduced bleeding time but not reversal of blood loss

Godier 2013

rabbit apixaban (IV)

rFVIIa PCC

Neither significantly decreased blood loss; rFVIIa partially reduced bleeding time

Perzborn 2013

baboon rivaroxaban rFVIIa PCC

aPCC

aPCC normalized bleeding time; rFVIIa partially decreased bleeding time

Khoo 2013

human dabigatran aPCC

aPCC normalized peak thrombin generation/lag time

Hinds 20

Appendix D

Table 18: Laboratory Assays for Assessment of NOACs35,37

Parameter Definition Application

Activated partial thromboplastin time

(aPTT)

Time from the addition of calcium to formation of a fibrin

clot

Linear response to dabigatran up to therapeutic dose (not quantitative in overdose)

Anti-Xa Measures the change in absorbance of specific clotting

factor Xa activity

Monitoring factor Xa inhibitors (if calibration and appropriate control agent available)

Clot formation time (CFT)

Speed of clot formation from 2 mm to 20 mm above baseline in

seconds

Prolonged by apixaban

Clotting time (CT) Measures conversion of fibrinogen to fibrin (time until

clot reaches 2 mm)

May be useful for dabigatran to steady-state levels; increased by rivaroxaban and apixaban

Ecarin clotting time (ECT)

Measures thrombin generation (ecarin activates prothrombin)

Most useful test for monitoring dabigatran; dose dependent increase when dabigatran present

Endogenous thrombin potential

(ETP)

Area under the curve, maximum amount of thrombin produced

Decreased by rivaroxaban and dabigatran

Lag time (LT) Time to start thrombin generation

Prolonged by dabigatran, rivaroxaban, apixaban

Maximum clot firmness (CFT)

Firmness of clot formed, strength of fibrin/platelet clot

Decreased by apixaban

Maximum concentration of thrombin (Cmax)

Maximum concentration of thrombin generated

Decreased by rivaroxaban

Prothrombin time (PT)

Time for plasma to clot after calcium and thromboplastin

added

Prolonged when dabigatran present (not as extensive as aPTT response); more responsive to

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 thrombin generation

Prolonged by apixaban, rivaroxaban, dabigatran

Other labs Complete blood count, serum creatinine

Hemoglobin/hematocrit and platelets (bleeding), creatinine clearance (renal function)

Coagulation assays and effect on patient outcomes not established; different reagents used in laboratory settings have different responsiveness