New Oral Anticoagulation Agents and Perioperative Considerations

Jerrold H. Levy, MD, FAHA, FCCMProfessor of Anesthesiology

Associate Professor of Surgery

CoDirector, Cardiothoracic ICU

Duke University School of Medicine

Durham, North Carolina

Disclosures for

Jerrold H Levy, MD, FAHA, FCCM

Research Support/P.I. DoD

Employee No relevant conflicts of interest to declare

Consultant No relevant conflicts of interest to declare

Major Stockholder No relevant conflicts of interest to declare

Speakers Bureau No relevant conflicts of interest to declare

Honoraria No relevant conflicts of interest to declare

Scientific Advisory BoardBoehringer-Ingelheim, CSL Behring, Grifols,

Janssen

COMPONENTS OF

HEMOSTASIS

•Vasculature

•Coagulation proteins

•Platelets

HemostasisSubendothelial matrix

Platelets

Hemostatic plug

Fibrin

Endothelial cell

RBC

WBCWBC

CLOT FORMATION

Fibrin

Red Blood Cell

Platelet

VASCULAR ENDOTHELIUMHuraux C et al: Circulation 1999;99:53-59

DIC• Triggered by TF/endothelial injury

• Produces fibrin deposition in microvasculature and MOS dysfunction

• Path: Microangiopathic hemolytic anemia

• Lab: platelets, fibrinogen, PT,

PTT, D-dimers, ATIII

PLATELET

INHIBITORS

PLATELET INHIBITORS

• Asprin

• Clopidogrel (Plavix), Prasugrel, Ticagralor

• ReoPro (abciximab)

• Integrilin (eptifibatide)

• Aggrastat (tirofiban)

PLATELET FUNCTION

EVALUATION• Platelet count

• Bleeding time

• Aggregation

• Platelet function assays: Multiplate, VerifyNow

• Experimental

Clopidogrel Mechanism of Action

ADP

Fibrinogen Binding Site

Fibrinogen Binding Reduced

Fibrinogen

Platelet

Herbert. Exp Opin Invest Drugs 1994;3:449-455.

Management of the Thienopyridine Treated Patient Requiring Surgery

• Delay surgery 5-7 days if possible• Caution with loading doses • Document the need for urgent surgery• ?Antifibrinolytics• Transfuse platelets if bleeding• Treat patient as a Glanzmann's

thrombasthenia if life threatening bleed.

Sniecinski and Levy: J Thorac Cardiovasc Surg 2011;142:662; Thromb Haemost. 2010;103(4):863 .

New Oral Anticoagulants

DOACs

TSOACs

Antithrombotics That Have Changed Clinical Practice

Anticoagulants• Low-molecular-weight heparin• Dabigatran, RivaroxabanAntiplatelet Drugs• Thienopyridines (clopidogrel,

prasugrel, ticagrelor)• Glycoprotein IIb/IIIa Inhibitors

Important Caveats:

Low Molecular Weight Heparin

• Half life prolonged with renal failure

• Measure antiXa levels to determine level

• Not reversible with protamine

• No currently available agents to reverse its anticoagulant effect

Levy JH: Anesthesiology. 2010;113(3):726-45 ; Levy JH: Surgery. 2007;142(4 Suppl):S71

New Oral Anticoagulants (NOACs)

• Oral Xa inhibitors: rivaroxaban

(Xarelto), apixiban (Eliquis)

• Oral thrombin inhibitors: dabigatran

(Pradaxa).

Levy JH: Anesthesiology. 2010;113(3):726-45 ; Levy JH: Surgery. 2007;142(4 Suppl):S71

VIIa

Xa

IXa

XIa

XIIa

Direct Thrombin inhibition

Tissue

factor

Factor IIa

(thrombin)Dabigatran

II

×

Dabigatran etexilate: oral DTI

• Dabigatran: prodrug is converted to active form – Binds clot-bound and free thrombin

with high affinity and specificity– Bioavailability: 6.5%– Renal excretion: 80%– Half-life: 12–17 hours– No interaction with food – Predictable anticoagulant effect– Fixed dose– No need for coagulation or platelet

monitoring

Pradaxa® (dabigatran etexilate). Summary of product characteristics. Apr 2008

20

Dabigatran etexilate

Monitoring Parameters

• Activated Partial Thromboplastin

Time (aPTT)

• Thrombin Time (TT)

• Diluted thrombin time (dTT)

• Ecarin Clotting Test (ECT)

Measuring Dabigatran: aPTT

Measuring Dabigatran: Thrombin Time

Measuring Dabigatran: Hemoclot

Measuring Dabigatran: INR

VIIa

Xa

IXa

XIa

XIIa

Direct Factor Xa inhibitionTissue

factor

Fibrinogen Fibrin clot

Factor II

(prothrombin)

Rivaroxaban

ApixabanEndoxaban

Betrixaban

×

Rivaroxaban: oral direct Factor Xa inhibitor

• Predictable pharmacology

• Half life 5-13 hrs • Low risk of drug–

drug interactions• Fixed dose• No requirement

for monitoring

Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005

Rivaroxaban® – rivaroxaban

N NO

NH

O

S

ClO

O

O

PT rivaroxaban

with 6 different thromboplastins

Samama MM et al, Thromb Haemost 2010; 103: 815-25

Laboratory Monitoring of Rivaroxaban

(and Apixaban)

Step 1: PT

–qualitative test (for screening)

–if elevated PT (and no other cause),

likely some rivaroxaban effect BUT,

highly assay-dependent

–if normal PT, no clinically significant

rivaroxaban effect

–for extra reassurance that no

residual anticoagulant effect…

MANAGING

BLEEDING

Warfarin-Associated Bleeding

ICH GI Bleed

• ICH accounts for ~5% of all

warfarin-related bleeds3

• Reported warfarin-related

ICH mortality rate ~50%1,4

• GI bleeds account for >60% of

warfarin-related bleeds1 and

~12% hospitalized for GI

bleeding have serious AEs2

1. Gomes T et al. CMAJ. 2012;DOI:10.1503/cmaj.121218. 2. Witt DM et al. Arch Intern Med. 2012;172:1484-1491.

3. Flaherty ML et al. Neurology. 2007;68:116-121. 4. Fang MC et al. Am J Med. 2007;120:700-705.

Options for reversing warfarin• Vitamin K

– Available orally or intravenous

– Readily available and inexpensive

– Response slow and unpredictable

– Not appropriate for emergencies

• Human plasma(e.g. FFP, 24-hour plasma)– Contains factors that are required and

some that are not required

– Risk of fluid overload and viral transmission

– Longer time required to thaw and transfuse the product

– Duration of infusion requires patient monitoring

– May fail to completely reverse anticoagulation

• Coagulation factor concentrates-PCCs(e.g. KCENTRA P/N)– Contain all clotting

factors required in a concentrate

– Fast application possible – Low volume – Predictable and

measurable effect• Recombinant FVIIa

– Off label use– Dose not established

Levy JH: Anesthesiology 2008 ;109(5):918

Correlation of INR With Factor Levels

Adapted with permission from Gulati G et al. Arch Pathol Lab Med. 2011;135:490-494.

Mean Factor Activity Levels vs INRF

acto

r A

cti

vit

y L

evels

{%

}

Mean

INR

II

VII

IX

X

1.25 1.8 2.3 2.8 3.3 3.8 4.3 4.8 5.3 5.8 6.3 7.05

120

100

80

60

40

20

0

• Practice guidelines for managing life-threatening, warfarin-related bleeding emphasize rapid VKA reversal3

• However, INR can decrease without changing the concentration of ALL clotting Factors with agents like FVIIa2

• INR, should not be considered the sole means of monitoring all the effects of warfarin reversal agents2

Warfarin Reversal and the Role of INR

1)Ansell J et al. Chest. 2008;133:160S-198S; 2) Freeman WD et al. Mayo Clin Proc. 2004;79:1495-1500. 3)Holbrook A et. al. Chest 2012: e152S-e184S

Anticoagulant reversal of warfarin by Beriplex®

-50

0

50

100

150

200

250

300

350

400

0 10 20 30 40 50

Th

rom

bin

nM

Time min

Control

PCC 0.72 U/ml

PCC 0.4 U/ml

PCC 0.2 U/ml

rFVIIa 60 nM

No Rx

Human plasma with INR≈5 spiked with PCC or rFVIIa T

hro

mbin

(nM

)

Tanaka et al. Thromb Res 2008; 122: 117–23INR, international normalised ratio; PCC, prothrombin complex concentrate; rFVIIa,

recombinant activated factor VII

Time (min)

36

PCCs and Factor Replacement Products1

1. Adapted with permission from Zareh M et al. West J Emerg Med. 2011;12:386-392. 2. Bebulin (Factor IX Complex) Prescribing

Information. Baxter Healthcare Corporation. July 2012. 3. Profilnine (Factor IX Complex) Prescribing Information. Grifols

Biologicals Inc. August 2011.

Vitamin K-dependent

coagulation factors

4-Factor

PCC*Plasma

4F-PCC activated(FEIBA))

3-Factor

PCC*rFVIIa

II †

VII† Low

levels2,3

IX †

X †

Protein C

Protein S

*Factors in PCCs are ~25x more concentrated than the factors in plasma.†In plasma, total content of factors relative to volume is low; large volumes are required for reversal.

activated activated

KCENTRA

Kcentra is approved as Beriplex®

outside the United States

37

•Kcentra is a non-activated 4F-PCC containing Factors II, VII, IX and X, and the antithrombotic Proteins C and S

•Kcentra is a lyophilized powder for IV infusion packaged with the necessary components for easy reconstitution

38

Kcentra

• Compared with plasma, Kcentra :• Non-inferior hemostatic efficacy• Superior to plasma in achieving INR

reduction to ≤1.3 at 30 min• Faster Factor replacement (˃50% levels at

30 min)• Requires 87% Less volume• Administered 7 x Faster

Summary: Efficacy and Administrationin Acute Major Bleeding

Kcentra Dosing and Administration

Baseline INRKcentra Dose* (units of Factor

IX/kg)

Maximum Dose†

(units of Factor IX)

2 to <4 25 Not to exceed 2,500

4 to 6 35 Not to exceed 3,500

>6 50 Not to exceed 5,000

*Dosing is based on actual potency as stated on the carton. †Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

Perioperative management:

NOACs

DOACs

TSOACs

Caveats:Dabigatran/Rivaroxaban

• For minor bleeding risk, consider continuing as if on warfarin or LMWH

• For urgent procedures, delay surgery 24-48 hours

• For emergent surgery, consider patients at increased risk of bleeding

• Avoid neuraxial procedures• Renal function will also determine

duration of effects

Dialysis?

Stopping Dabigatran PreOp

Renal function

CrCl

Half-life (hr)

Mean (range)

Time to stop:

Low risk of

bleed

Time to stop:

Hi risk of

bleed

> 80 13 (11 – 22) 1 d 2-4 d

50 – 80 15 (12 – 34) 1 d 2-4 d

30-50 18 (13 – 23) > 2 d >4 d

<30 27 (22 – 35) 2-5 d >5

Patients with bleeding on NOACs

Mild bleeding

Delay next dose or discontinue treatment as appropriate

Moderate/severe bleeding

Symptomatic treatment

Mechanical compression

Surgical intervention

Fluid replacement and hemodynamic support

Blood product transfusion

Oral charcoal application(if dabigatran etexilate ingested <2 hours before)

Hemodialysis

Life-threatening bleeding

Hemodynamic/ hemostatic resuscitation

PCC or activated PCC

Dialysis?

Managing bleeding with NOACs

Levy JH et al. Anesthesiology

2013;118:1466–74

Reversing NOACs with PCCs: what is the evidence?

• PCCs may have potential to reverse bleeding, based on animal and human studies.

• There is a lack of correlation between reversing laboratory tests and bleeding; extrapolating animal models and human volunteer data to bleeding patients should be cautiously interpreted.

• However, PCCs should be considered as part of a multimodal approach with hemodynamic and hemostatic resuscitation with major bleeding episodes

Zahir H: 2015 Jan 6;131(1):82-90; Dickneite G: TH 2014;111(2):189; Levy JH: Anesth 2013;118(6):1466;

Tanaka: BJA 2013;110(3):329

Reversing NOACs with PCCs: DATA• Eerenberg ES et al: Reversal of RIVA and DABI by PCC: a randomized,

placebo-controlled, crossover study in healthy subjects. Circulation.

2011;124(14):1573-9.

• Levi M et al: Comparison of 3-factor and 4-factor PCCs for reversal of the

anticoagulant effects of RIVA in volunteers. JTH 2014;12(9):1428-36.

• Zahir H et al. Edoxaban effects on bleeding following punch biopsy and

reversal by a 4-factor PCC. Circulation. 2015 Jan 6;131(1):82-90.

• Perzborn E et al: Reversal of RIVA anticoagulation with PCC, activated

PCCs and rFVIIa in vitro. Thromb Res 2014 Apr;133(4):671-81.

• Zhou W….Veltkamp R. Hemostatic therapy in experimental intracerebral

hemorrhage associated with rivaroxaban. Stroke. 2013 Mar;44(3):771-8.

• Marlu R et al. Effect of reversal on DABI and RIVA: a randomised

crossover ex vivo study in healthy volunteers. TH 2012;108(2):217-24

• Ansell JE et al: Use of PER977 to reverse the anticoagulant effect of

edoxaban. N Engl J Med. 2014 Nov 27;371(22):2141-2

Managing Bleeding NOACs/ Future

• Andexanet alfa (PRT4445):• FXa Inhibitor Antidote: Acts as FXa decoy-binds/

sequesters FXa inhibitors. Once bound to andexanet, inhibitors are unable to bind/ inhibit Factor Xa. (Blocking bleeding: reversing anticoagulant therapy. Nature Medicine, 19, 402–404 (2013)

• Preclinical and Phase 1 studies suggest andexanet can potentially be a universal reversal agent for all Factor Xa inhibitors (ISTH 2013 - AS 20.1: Crowther M et al)

49

Idarucizumab: Fab fragment to dabigatran

• Restoration of coagulation

– Potent binding: affinity ~350 times

higher than dabigatran to thrombin

– No procoagulant

– Short half-life

• Easy and rapid administration– IV administration, immediate onset

• Low risk of adverse reactions– No Fc receptor binding

– No endogenous targets

Idarucizumab is currently in development and is not approved for use in any country.

The information presented here is intended for medical education purposes only

IV = intravenous

Glund S et al. AHA 2013; abstract 17765;

van Ryn J. AHA 2012; Presentation 9928; van Ryn J et al. Circulation 2012;126:A9928

Fully humanized

antibody fragment

(Fab)

Volunteer study: immediate, complete, and sustained reversal of

dabigatran anticoagulation

Idarucizumab is currently in development and is not approved for use in any country. The information presented here is intended for medical education purposes only

‘Normal upper reference limit’ refers to (mean+2SD) of 86 predose measurements from a total of 51 subjects

Glund S et al. AHA 2013; abstract 17765

Dabigatran plus:

Placebo (n=9)

1 g idarucizumab (day 4) (n=9)

2 g idarucizumab (day 4) (n=9)

4 g idarucizumab (day 4) (n=8)

Normal upper reference limit (n=86)

Mean baseline (n=86)

51

End of idarucizumab injection (5 min infusion)

Dabigatran + placebo

–2

Time after end of infusion (hours)

dTT

(s)

DabigatranAntidote

70

65

60

55

50

45

40

35

30

0 2 4 6 8 10 12 24 36 48 7260

Healthy volunteer study: conclusions

• Doses up to 8 g idarucizumab (or placebo) were

administered to 145 healthy male volunteers

• Idarucizumab infusion led to immediate, complete,

and sustained reversal of dabigatran anticoagulant

activity witout prothrombotic effects as indicated by

the ETP

• Idarucizumab was safe and well tolerated, both alone

and in combination with dabigatran

Idarucizumab is currently in development and is not approved for use in any country.

The information presented here is intended for medical education purposes only

ETP = endogenous thrombin potential

Glund S et al. AHA 2013; abstract 17765 52

Trial of a NOAC-specific antidote

Study to evaluate reversal of the anticoagulant effects of dabigatran with idarucizumab in:

Bleeding patients – overt bleeding judged by the physician to

require a reversal agent

Surgical patients – require an emergency surgery or procedure for a

condition other than bleeding

Idarucizumab is currently in development and is not approved for use in any country. The information

presented here is intended for medical education purposes only

NCT02104947: Available at http://www.clinicaltrials.gov/ct2/show/NCT02104947; Accessed August 2014

Started in April 2014, currently recruiting in >35 countries worldwide

Bleeding and management of

coagulopathy.

Sniecinski RM, Levy JH.

J Thorac Cardiovasc Surg. 2011

Sep;142(3):662-7.

Treating Bleeding (1)

• Send coagulation tests: TEG and ROTEM too if possible

• Check fibrinogen and platelet count• If PTT elevated, protamine < 25 mg• If still bleeding, consider platelets but

check fibrinogen-Fibrinogen (cryo) corrects platelet dysfunction

• ?DDAVP; but ~Vasopressin?

Treating Bleeding (2)

• Treat anemia; may contribute to bleeding

• Consider antifibrinolytics: tranexamic acid

• With massive bleeding, initiate massive transfusion protocol

• Any transfusion algorithm will be useful and should be established on an institutional basis

Copyright restrictions apply.

Tanaka, K. A. et al. Anesth Analg 2008;106:732-738

Thromboelastography recordings obtained with the ROTEM(R) device after the addition of rFVIIa and/or fibrinogen in the presence

of tissue type plasminogen activator in volunteer plasma

Managing anticoagulants: summary

• Stop anticoagulant, but risk vs benefit• Check coagulation tests if possible to

determine effect• Risk vs benefit to reverse Warfarin: PCC vs

FFP, Vitamin K• Oral Xa inhibitors: PCCs• Dabigatran: activated PCCs• ? Factors: normalize fibrinogen• ?Antifibrinolytics

Crowther MA: Blood 2008; 111:4871; J Thromb Haemost 2009;7 Suppl 1:107; van Ryn J: Thromb Haemost

2010;103(6):1116; Eerenberg: Circulation. 2011;124(14):1573; Levy JH: Lancet 2010;376(9734):3

Summary

• The use of Rx that affect hemostasis is increasing

• Newer agents do not have active reversal strategies; need to stop Rx but then again neither does LMWH or antiplatelet agents

• Increasing data is evolving to manage life threatening hemorrhage with these novel agents.