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Alexander G G TurpieProfessor Emeritus of Medicine

McMaster UniversityHamilton ON

Canada

Update on NOACsUpdate on NOACs

Disclosures for Dr A G Disclosures for Dr A G GG TurpieTurpie

Research Support None

Employee None

Consultant and/or Honoraria

Bayer HealthCare, Boehringer-Ingelheim, Bristol-Myers Squibb, Johnson and Johnson, Sanofi-Aventis, Takeda, Portola

Stockholder None

Speakers Bureau Pfizer, GSK

Scientific Advisory Board

Bayer HealthCare, Johnson and Johnson,

Streptokinase

EVOLUTION OF ANTITHROMBOTICSEVOLUTION OF ANTITHROMBOTICS

Parenteral

Oral

20101960 1970 1980 1990 2000

Heparin

Warfarin

LMWH’s

Direct Thrombin

Inhibitors

Indirect FXa

Inhibitors

Direct Thrombin

InhibitorsDirect FXa

Inhibitors

Adapted from: Weitz J, Hirsh J. Chest. 2001;119:95S; Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990

1962 2014

Clopidogrel

Aspirin

Streptokinase

EVOLUTION OF ANTITHROMBOTICSEVOLUTION OF ANTITHROMBOTICS

Parenteral

Oral

20101960 1970 1980 1990 2000

Heparin

Warfarin

LMWH’s

Direct Thrombin

Inhibitors

Indirect FXa

Inhibitors

Direct Thrombin

InhibitorsDirect FXa

Inhibitors

Adapted from: Weitz J, Hirsh J. Chest. 2001;119:95S; Alban. Eur J Clin Invest 2005; Link. Circulation 1959; Maraganore et al. Biochemistry 1990

1962 2014

Clopidogrel

Aspirin

2014

NOACs

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New anticoagulantsNew anticoagulants

TFPI (tifacogin)

FondaparinuxIdrabiotaparinux

RivaroxabanApixabanDarexabanEdoxabanBetrixaban

Dabigatran

ORAL PARENTERAL

DX-9065aOtamixaban

Xa

IIa

TF/VIIa

X IX

IXaVIIIa

Va

II

FibrinFibrinogen

AT

APC (drotrecogin alfa)sTM (ART-123)

Adapted from Weitz & Bates, J Thromb Haemost 2005

TTP889

What is the Better Target?What is the Better Target?

AntiAnti--XaXa AntiAnti--IIaIIa

Gatekeeper of the Gatekeeper of the coagulation cascadecoagulation cascade

Final common Final common pathwaypathway

Blocks amplificationBlocks amplification Block thrombin Block thrombin activityactivity

Blocks thrombin Blocks thrombin generationgeneration

Block Contact Block Contact ActivationActivation

Preserves hemostatic Preserves hemostatic mechanismsmechanisms

Block Block platelet activationplatelet activation

New AnticoagulantsNew Anticoagulants

Direct Thrombin InhibitorsDirect Thrombin Inhibitors

-- DabigatranDabigatranFactor Xa InhibitorsFactor Xa Inhibitors

-- RivaroxabanRivaroxaban

-- ApixabanApixaban

-- EdoxabanEdoxaban

Comparative PharmacologyComparative Pharmacology

Characteristic Rivaroxaban Apixaban Edoxaban Dabigatran

Target Factor Xa Factor Xa Factor Xa Thrombin

Prodrug No No No Yes

Bioavailability 80% -100% 60% 50% 6%

Dosing o.d. (b.i.d.) b.i.d. o.d. b.i.d. (o.d.)

Half-life 7-11 h 12 h 9-11 h 12-14 h

Renal 36% (66%) 25% 35% 80%

Monitoring No No No No

Interactions 3A4/P-gp 3A4 3A4/P-gp P-gp

P-gp=P-glycoprotein

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New AnticoagulantsNew Anticoagulants

�� VTE PreventionVTE Prevention

�� VTE TreatmentVTE Treatment

�� Stroke Prevention in AFStroke Prevention in AF

�� Secondary Prevention of Secondary Prevention of ACSACS

Venous ThromboembolismVenous Thromboembolism

ACCP = American College of Chest Physicians; INR = international normalized ratio; IVC = inferior vena cava.

Kearon C et al. Chest. 2012;141(2 suppl):e419S-e494s.

Initial treatment

Long-term treatment

Extended treatment

Bridging therapyVKAs (INR 2.3-3.0) or parenteral anticoagulant

Parenteral anticoagulant and VKA (INR 2.3-3.0)

HeparinLMWHFondaparinuxThrombolysis Thrombus removal IVC filter

Treatment of VTE: Treatment of VTE: 9th Edition ACCP Guidelines9th Edition ACCP Guidelines

VKAs (INR 2.3-3.0) or parenteral anticoagulant

1. Kearon C et al. Chest. 2012;141(2 suppl):e419S-e494s. 2. Goldhaber SZ, Bounameaux H. Lancet. 2012;379(9828):1835-1846.

Initial treatment

Evolution of VTE TreatmentEvolution of VTE Treatment

Switching2

Single drug approach2

0 to ~7 days

Initial treatment

Long-term treatment

Extended treatment

Bridging therapy

~3 months to indefinite~7 days to ~3 months

VKAs (INR 2.3-3.0) or parenteral anticoagulant

Parenteral anticoagulant and VKA (INR 2.3-3.0)

VKAs (INR 2.3-3.0) or parenteral anticoagulant

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Evolving Anticoagulation StrategiesEvolving Anticoagulation Strategies

OverlappingOverlapping

SwitchingSwitching

Oral Oral MonotherapyMonotherapy

LMWH/Warfarin Bridge

UFH/Warfarin Bridge

LMWH to Dabigatran

(RE-COVER)

LMWH to Edoxaban(HOKUSAI)

(N=8,250)

Rivaroxaban(3 week loading dose)

(EINSTEIN)

Apixaban (1 week load)

(AMPLIFY))

Agent Trial

Dabigatran RECOVER, REMEDY, RESONATE

Rivaroxaban EINSTEIN-DVT, PE, EXTENSION

Apixaban AMPLIFY, AMPLIFY-EXT

Edoxaban HOKUSAI

Trials of New AnticoagulantsVersus Warfarin for VTE Treatment

Apixaban Edoxaban Dabigatran Rivaroxaban

RecurrentVTE

Major bleeding

Intracranial hemorrhage

Mortality

New OACs Compared to Standard of Care for VTE

Who May Be Candidates for Who May Be Candidates for Outpatient Therapy?Outpatient Therapy?

�� The decision to treat a patient with The decision to treat a patient with DVT or PE in the outpatient setting is DVT or PE in the outpatient setting is based on numerous factors:based on numerous factors:–– Adequate home circumstancesAdequate home circumstances

–– Risk factors for recurrence and/or Risk factors for recurrence and/or bleedingbleeding

��Risk stratification tools may aid in Risk stratification tools may aid in patient selectionpatient selection

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Treatment of VTETreatment of VTE

• NOACs have greatly facilitated outpatient management of VTE

• Some NOACs have eliminated the need for parenteral administration of anticoagulants for majority of patients with acute VTE

• Risk stratification useful in management of PE including duration of hospitalisation

• New ESC PE Guidelines presented at ESC 2014

Stroke Prevention in AFStroke Prevention in AF

Anticoagulation in AFAnticoagulation in AFStroke Risk ReductionsStroke Risk Reductions

Hart et al. Hart et al. Ann Intern MedAnn Intern Med. 1999;131:492. 1999;131:492--501.501.

Warfarin BetterWarfarin Better Control BetterControl Better

AFASAKAFASAK

SPAFSPAF

BAATAFBAATAF

CAFACAFA

SPINAFSPINAF

EAFTEAFT

100%100% 50%50% 00 --50%50% --100%100%

AggregateAggregate

Reduction of Reduction of StrokeStroke

RRR 64% RRR 64%

Reduction of Reduction of StrokeStroke

RRR 64% RRR 64%

Reduction ofReduction ofAllAll--Cause Mortality Cause Mortality

RRR 26%RRR 26%

Reduction ofReduction ofAllAll--Cause Mortality Cause Mortality

RRR 26%RRR 26%

MEDICATIONMEDICATION ACTIONACTIONPHASE III PHASE III

TRIALTRIALCOMPARATORCOMPARATOR DESIGNDESIGN nn

DabigatranDabigatran DTIDTI RERE--LYLY WarfarinWarfarinNonNon--inferiorityinferiority

18 11318 113

ApixabanApixaban Anti XaAnti XaAVERROESAVERROES Aspirin Aspirin SuperioritySuperiority 5 5995 599

ARISTOTLEARISTOTLE WarfarinWarfarinNonNon--inferiorityinferiority

18 20118 201

RivaroxabanRivaroxaban Anti XaAnti Xa ROCKET AFROCKET AF WarfarinWarfarinNonNon--inferiorityinferiority

14 20414 204

EdoxabanEdoxaban Anti XaAnti Xa ENGAGE AFENGAGE AF WarfarinWarfarinNonNon--inferiorityinferiority

21 10521 105

Direct Thrombin Inhibitors and Factor Xa Inhibitors for AF

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New OACs TrialsNew OACs TrialsAllAll--cause Stroke or Systemic Embolismcause Stroke or Systemic Embolism

Connolly SJ, et al. N Engl J Med. 2009; 361:1139−51.Patel MR, et al. N Engl J Med. 2011; 365:883−91.Granger CB, et al. N Engl J Med. 2011; 365:981−92.

WarfarinBetter

New AnticoagulantBetter

0.5 1.0 2.0

Apixaban 5mg BID

Rivaroxaban 20mg QD

Dabigatran 150mg BID

Dabigatran 110mg BIDRE-LY

ROCKET AF

ARISTOTLE

TRIAL OAC Agent RRR (95% CI) P Value#

P = 0.01

P = 0.30

P < 0.001

P = 0.12

Not head-to-head comparisons

New OACs are consistently associated with a lower or similar risk of stroke or systemic embolism

Efficacy vs SafetyEfficacy vs SafetyNOAC 4NOAC 4--trial Metatrial Meta--analysis Full Doseanalysis Full Dose

Ruff C, et al. Lancet 2013

Result

Pooled

DOACPooled

Warfarin Risk Ratio

95% CIs

pEvents/Total

Events/Total

EfficacyIschaemic Stroke

665/29292

724/29221

0.920.83-1.02

0.10

Hemorrhagic stroke

130/29292

263/29221

0.490.38-0.64

<0.0001

Myocardial Infarction

413/29292

432/29221

0.970.78-1.20

0.97

All Cause mortality

2022/29292

2245/29221

0.900.851-0.95

0.0003

SafetyIntra-cranial hemorrhage

204/29287

425/29211

0.480.39-0.59

<0.0001

Gastrointestinal bleeding

751/29287

591/29211

1.251.01-1.55

0.043

Favours NOAC 1 20.25

Guidelines for AF ManagementGuidelines for AF Management

1. 1. ESC Guidelines: ESC Guidelines: CammCamm AJ, et al. AJ, et al. EurEur Heart J.Heart J. 2010;31:23692010;31:2369––429. 429. 2. 2. CammCamm AJ, et al. AJ, et al. EuropaceEuropace. . 2012;14(102012;14(10):):13851385--413. 413. 3. 3. ACCF/AHA/HRS Guidelines: ACCF/AHA/HRS Guidelines: WannWann LS, et al. LS, et al. J Am J Am CollColl CardiolCardiol.. 2011;57:13302011;57:1330––1337. 1337. 4. 4. CCS Guidelines: CCS Guidelines: SkanesSkanes AC, et al. AC, et al. Can J Can J CardiolCardiol.. 2012;28:1252012;28:125––136. 136. 5. 5. You JY, et al. ACCP Guidelines: You JY, et al. ACCP Guidelines: Chest 2012;141;e531SChest 2012;141;e531S––e575S; e575S; http://www.nice.org.uk/ta249http://www.nice.org.uk/ta249..

AF = atrial fibrillation

Guidelines for Stroke Guidelines for Stroke Prevention Patients with NVAF Prevention Patients with NVAF Guidelines

StrokeRisk

Scoring System

High RiskIntermediate

RiskLow Risk NOACs

2014 ACC/AHA/HRS1

CHA2DS2-VASc

OAC OAC, aspirin, or no treatment

No antithrombotic

NOACs as an alternative to warfarin

2012 ESC2 CHA2DS2-VASc

OAC OAC No antithrombotic

NOACs are broadly preferred over VKA in the vast majority of patients

with NVAF when used as studied in clinical trials

2012 ASA/AHA3 CHADS2 OAC OAC or aspirin Aspirin NOACs as an alternative

to warfarin

2012 ACCP4 CHADS2 OAC

OAC or dual

antiplatelet therapy

(OAC preferred)

No antithrombotic

Dabigatran should be considered over VKA*

1. January CT, et al. Circulation. 2014. [Epub ahead of print] 2. Camm AJ, et al. Eur Heart J. 2012;33:2719-2747. 3. Furie KL, et al. Stroke.2012;43:3442-3453. 4. You JJ, et al. Chest. 2012;141 (Suppl):e531S-e575S.

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GARFIELD ‒ TGARFIELD ‒ To describe realo describe real--life treatment patterns in newly life treatment patterns in newly diagnosed patients with atrial fibrillation and at least one diagnosed patients with atrial fibrillation and at least one additional risk factor for strokeadditional risk factor for stroke

Europe: Austria, Denmark, Finland, France, Germany, Italy, Netherlands, Norway, Poland, Spain, Sweden, United Kingdom

Belgium, Czech Republic, Hungary, Russia, Switzerland, Ukraine

Asia-Pacific: Australia, China, Japan, Korea India, Singapore, Thailand

The Americas: Canada, Brazil, Mexico Argentina, Chile, United States

Africa: South Africa

Middle East: Turkey, United Arab Emirates

Cohort 1 Cohort 2 & 3

21st March 2014: 34 countries active in cohort 3; 30,070 patients enrolled

GARFIELDGARFIELD--AF: Evolution of anticoagulant AF: Evolution of anticoagulant and and antianti--platelet platelet treatment treatment patterns at AF diagnosis (2009‒2013)patterns at AF diagnosis (2009‒2013)

VKA, Vitamin K antagonists; FXa, Factor Xa inhibitors; DTI, Direct thrombin inhibitors; AP, Antiplatelets.

N=10,302 N=11,595 N=4305

60.5 % 62.3 %67.3 %

Proportion of patients receiving Factor Xa Proportion of patients receiving Factor Xa inhibitors and inhibitors and ddirect thrombin inhibitorsirect thrombin inhibitors

6.2

2.0

6.7

15.0

5.0

1.1

7.0

9.3

Total (n=26,356) Cohort 1 (n=10,453) Cohort 2 (n=11,595) Cohort 3 (n=4308)

Factor Xa inhibitors

Direct thrombin inhibitors

Preliminary data, 5 December 2013

Future ChallengesFuture Challenges

�� Management of bleedingManagement of bleeding

-- PreventionPrevention

-- TreatmentTreatment

�� MeasurementMeasurement

�� AntidotesAntidotes

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All anticoagulants can All anticoagulants can cause bleedingcause bleeding

Bleeding in VKA Bleeding in VKA anticoagulatedanticoagulated patientspatients

�� Is common Is common –– Major bleeding 1Major bleeding 1--5% per year in AF5% per year in AF–– Intracranial bleeding 0.5Intracranial bleeding 0.5--1.2% per year in AF1.2% per year in AF

�� Associated with adverse outcomesAssociated with adverse outcomes

–– 3 to 53 to 5--fold increase in thrombotic events & death fold increase in thrombotic events & death

�� Rapid and timely control of bleeding is likely Rapid and timely control of bleeding is likely to improve clinical outcomes but the efficacy to improve clinical outcomes but the efficacy of anticoagulant reversal is unprovenof anticoagulant reversal is unproven

Management of Management of bleedingbleeding

��PreventionPrevention��TreatmentTreatment

Prevention of bleedingPrevention of bleeding��Anticoagulant selectionAnticoagulant selection

��Patient and dose selection Patient and dose selection ��Appropriate management of Appropriate management of

interruptioninterruption

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NOAC Trials NOAC Trials -- Major BleedingMajor Bleeding

WarfarinBetter

New AnticoagulantBetter

0.5 1.0 2.0

P = 0.31

P = 0.003

P = 0.58

P < 0.001

HR (95% CI) P Value#

Apixaban 5mg BID

Rivaroxaban 20mg QD

Dabigatran 150mg BID

Dabigatran 110mg BIDRE-LY

ROCKET AF

ARISTOTLE

TRIAL OAC Agent

New OACs are associated with a lower or similar risk of major bleeding

Connolly SJ, et al. N Engl J Med. 2009; 361:1139−51.Patel MR, et al. N Engl J Med. 2011; 365:883−91.Granger CB, et al. N Engl J Med. 2011; 365:981−92.

Not head-to-head comparisons

NOAC NOAC vsvs WarfarinWarfarin: : Major GI BleedingMajor GI Bleeding

*Rivaroxaban: *% and not %/yr are reported; RR, not reported, was calculated: http://www.spc.univ-lyon1.fr/mfcalc Connolly SJ, et al. N Engl J Med 2010; 363(19):1875-1876, suppl app. Patel MR, et al. N Engl J Med. 2011; 365:883−91.Granger CB, et al. N Engl J Med. 2011; 365:981−92.

105 (0.76)

119 (0.86)

224 (3.15)

154 (2.16)

NOAC Warfarin

0.5 1.0

Favours NOAC Favours warfarin

HR

0.89

1.46

137 (1.15)

126 (1.07)

1.08

1.50.0

188 (1.56)

126 (1.07)

1.48

No. of events (% yr)

2.0

Dabigatran 110

Rivaroxaban*

Apixaban

Dabigatran 150

Not head-to-head comparisons

New OACs are associated with a similar or higher risk of GI bleeding

NOACs TrialsNOACs Trials--Intracranial HemorrhageIntracranial Hemorrhage

Not head-to-head comparisons

WarfarinBetter

1.0

Apixaban 5mg BID

Rivaroxaban 20mg QD

Dabigatran 150mg BID

Dabigatran 110mg BID

RE-LY

ROCKET AF

ARISTOTLE

TRIAL OAC Agent HR (95% CI) P Value#

P < 0.001

P < 0.001

P < 0.001

P = 0.02

0.25 0.50 0.75

NOACs are consistently associated with a lower risk of intracranial hemorrhage

New AnticoagulantBetter

Connolly SJ, et al. N Engl J Med. 2009; 361:1139−51.Patel MR, et al. N Engl J Med. 2011; 365:883−91.Granger CB, et al. N Engl J Med. 2011; 365:981−92.

Dabigatran vs. warfarin is associated with better Dabigatran vs. warfarin is associated with better outcomes after bleeding outcomes after bleeding

The Kaplan–Meier analysis suggest a reduced risk for death with dabigatran vs warfarin during 30 days after the bleeding (P=0.052)

Mor

talit

y ra

te (

%)

Time (days)

0

0.1

0.2

0.3

5 10 15 20 25 30 35

WarfarinDabigatran

Majeed A, et al. Circulation 2013

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Apixaban Apixaban vsvs warfarin is associated with better warfarin is associated with better outcomes after bleeding outcomes after bleeding

Hylek EM et al. Presented at: American Heart Association. November 2012. Los Angeles, CA. Abstract 15115.

0

10

20

30

40

50

60

70

80

Nu

mb

ero

f pat

ien

tsex

per

ien

cin

gm

ajo

rb

leed

ing

follo

wed

by

dea

thin

30

day

s

Major bleeding followed by death within 30 days

HR= 0.50(95% CI 0.33-0.75; p<0.001)

35 patients(n=9,088)

69 patients(n=9,052)

Apixaban Warfarin

Perioperative Management of NOACPerioperative Management of NOAC--treated Patientstreated Patients

Management of Management of Interruption of Treatment Interruption of Treatment

Drug Patient Procedure

Drughalf-life

Renal function

Bleeding risk

Route of clearance

Concomitant drugs (e.g., aspirin)

Thrombosis risk

Last intake of drug before elective surgical intervention

Creatinine clearance (CrCl)

Dabigatran Apixaban Rivaroxaban

No important bleeding risk and/or adequate local haemostasis possible:Perform at trough level (i.e. 12 h or 24 h after last intake)

Low risk High risk Low risk

High risk

Low risk

High risk

CrCl ≥80 ml/min ≥24 h ≥48 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 50-80 ml/min ≥36 h ≥72 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 30-50 ml/min* ≥48 h ≥96 h ≥24 h ≥48 h ≥24 h ≥48 h

CrCl 15-30 ml/min* Not indicated

Not indicated ≥36 h ≥48 h ≥36 h ≥48 h

CrCl <15ml/min No official indication for use

Heidbuchel et al, 2013

*Many of these patients may be on lower dose of NOACLow risk = surgery with low risk of bleeding, high risk = surgery with high risk of bleeding

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ProcedureProcedure ActionActionProcedures with immediate and complete haemostasis:

Atraumatic spinal/ epidural anaethesiaClean lumbar puncture

Resume 6–8 h after surgery

Procedures associated with immobilization

Initiate reduced venous or intermediate dose of LMWH 6–8

h after surgery if haemostasis achieved

Procedures with post-operative risk of bleeding

Restart NOACs 48–72h after surgery upon complete

haemostasisThromboprophylaxis (e.g. with LMWH) can be initiated 6-8 h

after surgeryHeidbuchel et al, 2013

Resumption of NOACTreatment of bleedingTreatment of bleeding��Measurement of Anticoagulant Measurement of Anticoagulant

effecteffect��General General measuresmeasures

��Reversal Reversal of anticoagulationof anticoagulation

Monitoring Monitoring vsvs MeasuringMeasuring■■Monitoring implies dose adjustment according to Monitoring implies dose adjustment according to

test resulttest result

■■Measuring the drug or drug effect may be useful in:Measuring the drug or drug effect may be useful in:• Overdosage• Questions of compliance• Urgent surgery, interventions, thrombolysis• Extreme body weights• Children• Renal insufficiency

Measurement of anticoagulant Measurement of anticoagulant effects of NOACseffects of NOACs

TestTest DabigatranDabigatran RivaroxabanRivaroxaban ApixabanApixaban

Specific Specific AssayAssay

Drug Drug specificspecific

HemoclotHemoclot AntiAnti--XaXa AntiAnti--XaXa

NonNon--specific specific assaysassays

aPTTaPTT ↑↑↑↑↑↑ ↑↑ ↑↑

PTPT ↑↑ ↑↑↑↑ ↑↑

TTTT ↑↑↑↑↑↑↑↑ No effectNo effect No effectNo effect

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SUBJECT:RIVAROXABAN ANTI XA LEVELSDATE: JANUARY 23, 2015

Our Special Coagulation laboratory is pleased to inform you that we have added Rivaroxaban anti Xa levels to our test menu

FutureFuture

Point of care testingPoint of care testing

Management of VKA Bleeding Management of VKA Bleeding

��Hold drug(s)Hold drug(s)

�� Vitamin KVitamin K��Resuscitation (Resuscitation (i.v.i.v. access, fluid access, fluid

administration, blood product administration, blood product transfusion) transfusion)

��Maintain diuresis to clear drugMaintain diuresis to clear drug

��Mechanical compression and Mechanical compression and surgical methods to stop bleedingsurgical methods to stop bleeding

Replace clotting factorsReplace clotting factors

Characteristic Frozen plasma PCC

Constituents All clotting factors II, (VII), IX, X (C, S)

Dose 10-15 ml/kg 25-50 IU factor IX/kg

Onset Duration of infusion 15-30 min

Adverse effectsFluid overload, febrile & allergic reactions,

infection, TRALI

Possible excess thromboemboliccomplications

OtherVitamin K to

sustain reversal*Vitamin K to

sustain reversal*

Quinlan D, et al. Circulation 2013; 128:1179-81.

*Half life of factor VII is 6 hours

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Frozen Plasma or PCC?Frozen Plasma or PCC?

Sarode R, et al. Circulation 2013; 128:1234-1243.

Management of NOAC Bleeding Management of NOAC Bleeding

�� Hold drug(s)Hold drug(s)

�� No No VitVit KK

�� Resuscitation (Resuscitation (i.v.i.v. access, fluid access, fluid administration, blood product administration, blood product transfusion) transfusion)

�� Maintain diuresis to clear drugMaintain diuresis to clear drug

�� Mechanical compression and surgical Mechanical compression and surgical methods to stop bleedingmethods to stop bleeding

Reversal of NOACReversal of NOACss

��Activate Activate coagulation to coagulation to overcome the effect of the drugovercome the effect of the drug

��Remove Remove drugdrug��Neutralize drug Neutralize drug

Lauw M, et al. Can J Cardiol 2014 (accepted).

Activate coagulationActivate coagulation

�� Prothrombin complex concentrates (PCC)Prothrombin complex concentrates (PCC)–– II, VII, IX, X, C, S, II, VII, IX, X, C, S, –– 2525--50 units per kg 50 units per kg

�� Activated prothrombin complex concentrates Activated prothrombin complex concentrates (aPCC)(aPCC)

�� ((AntifibrinolyticAntifibrinolytic agents (e.g., tranexamic acid) agents (e.g., tranexamic acid)

�� Recombinant factor Recombinant factor VIIaVIIa ((rVIIarVIIa))

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ProthrombinProthrombin time (PT)time (PT)Endogenous thrombin Endogenous thrombin

potential (ETP)potential (ETP)

Eerenberg et al, 2011

� PCC demonstrated the potential to reverse rivaroxabaneffects on PT and ETP in humans

Rivaroxaban : Effect on Prothrombin Time and Endogenous Thrombin Potential with PCC Antidotes to AnticoagulantsAntidotes to Anticoagulants

�� BleedingBleeding

�� Emergency InterventionEmergency Intervention�� Elective InterventionElective Intervention

��OverdoseOverdose

Specific antidotes to NOACSpecific antidotes to NOACss

Idarucizumab PER977 Andexanet alpha

StructureHumanized

Fab fragment

Synthetic small

molecule

Human rXa variant

Target Dabigatran Universal FXa inhibitors

Binding Non-competit.High affinity

? Competitive

Clinicalstudies

Rapid complete reversal

?Rapid, near completereversal

Lauw M, et al. Can J Cardiol 2014 (accepted).

EnoxAlone

Enox + Antidote

Tail Transection

No Enox

Antidote Bolus

Source: Portola Pharmaceutical Data on File; Genmin Lu, Ph.D ESC 2011 Oral Presentation

% Reversal of rivaroxabanin vitro

Antidote (µM)Minutes

Reversal of Blood Loss (µL) in rat model

Andexanet Alpha– A Universal fXa antidote that binds Xa and neutralizes catalytic prothrombinase reaction

Universal binding activity to Xa inhibitors

� Immediate onset of action

� No procoagulant or anticoagulant activity

� Estimated human half-life of 90 minutes

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Phase 2 Clinical Study OverviewPhase 2 Clinical Study OverviewDouble blind, randomized 2:1 (9 healthy subjects per cohort)Double blind, randomized 2:1 (9 healthy subjects per cohort)

Factor XaInhibitor

Days 1-6 (to steady state)

PRT064445/Placebo IV

Day 63h after last fXa inhibitor dose

Study 1: Apixaban 5 mg PO Q12 Study 2: Rivaroxaban 20 mg PO QD Study 3: Enoxaparin 1 mg/kg SQ Q12 Study 4: Betrixaban 80 mg PO QDStudy 5: Edoxaban TBD

Study 1 - ApixabanCohort 1: 90 mg IV x 1 Cohort 2: 210 mg IV x 1 Cohort 3: 420 mg IV x 1 Cohort 4: TBD

Checkout Inpatient

Unit

Last Safety

f/u

Day 13 Day 48

Dose-Dependent Reversal of Apixaban-induced Anti-FactorXa Activity Correlates with Reduction in

Apixaban Plasma Free Fraction

Mean ± SEM

Anti-fXa activity Apixaban free fraction

AndexanetAndexanet AlphaAlpha

�� FDA designated breakthrough therapyFDA designated breakthrough therapy

�� Phase III Clinical TrialsPhase III Clinical Trials

-- ANNEXAANNEXA--A : A : apixabanapixaban

-- ANNEXAANNEXA--R : R : rivaroxabanrivaroxaban

-- ANNEXAANNEXA--E : E : edoxabanedoxaban

� FDA-designated breakthrough therapy.

� Universal antidote for patients receiving a Factor Xa inhibitor anticoagulant who suffer a major bleeding episode or who may require emergency surgery

� Under development

AndexanetAndexanet AlphaAlpha

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ConclusionsConclusions�� NOACs provide opportunity to minimize growing NOACs provide opportunity to minimize growing

burden of potentially preventable thromboembolism burden of potentially preventable thromboembolism (especially AF)(especially AF)

�� Reductions in both stroke and bleeding translate into Reductions in both stroke and bleeding translate into important benefits for patientsimportant benefits for patients

�� Most bleeding can be managed without specific Most bleeding can be managed without specific antidotes antidotes

�� Specific antidotes in development will provide Specific antidotes in development will provide reassurance to physicians reassurance to physicians

�� Education to overcome the fear of bleeding as a Education to overcome the fear of bleeding as a barrier to appropriate anticoagulant use importantbarrier to appropriate anticoagulant use important