AF – New Anticoagulants: Todays Aims

W

D E A R

1. Characterize the new AC

2. Know critical differences

3. Know the latest study findings in AF

4. Ask critical questions on TTR, OAC naive pts

Compliance and dosing intervals, future devel.,

CHADS2 scores, previous stroke, CCr, age,

monitoring to Drs Conolly and Brunckhorst

B

Aspirin

Stroke Prevention in AF – New Anticoagulants

W

D E A R

B

Aspirin

„Plasmatic“ „Platelet“

Rivaroxaban*

Apixaban*

Otamixaban

Edoxaban*

Betrixa Eribaxa.…

vWF

ADP

LMWH/UFH

Fondaparinux

[Idraparinux]

Idrabiotaparinux

Aspirin

Platelet

activation

Secretion

P2Y12R

TxA2

TxA2R

Endothelial

Lesion

GP

II b

GP

III

a

Activation

Cangrelor

Ticagrelor

Clopidogrel

Prasugrel

Elinogrel

GP

II b

GP

III

a

GP

II b

GP

III

aPlatelet-Fibrinogen-

Network

Fibrin FibrinogenAbxicimab

Tirofiban

Eptifibatide

IX

IXa

VIIIa

XIa

GP

II b

GP

III

a

II

IIa

LMWH/UFH

Bivalirudin

Lepirudin

Dabigatran*

[Ximelagatran]

AZD0837

SCH530348

ADP

TxA2

Terutruban

E5555

GP

Ia/IIa GP Ib/IX/V

Ge

bh

ard

& B

ee

r 2

01

0

aFIXa aptamer

avWF aptamer

aFXI

„Plasmatic“ „Platelet“

Rivaroxaban*

Apixaban*

Otamixaban

Edoxaban*

Betrixa Eribaxa.…

vWF

ADP

LMWH/UFH

Fondaparinux

[Idraparinux]

Idrabiotaparinux

Aspirin

Platelet

activation

Secretion

P2Y12R

TxA2

TxA2R

Endothelial

Lesion

GP

II b

GP

III

a

Activation

Cangrelor

Ticagrelor

Clopidogrel

Prasugrel

Elinogrel

GP

II b

GP

III

a

GP

II b

GP

III

aPlatelet-Fibrinogen-

Network

Fibrin FibrinogenAbxicimab

Tirofiban

Eptifibatide

IX

IXa

VIIIa

XIa

GP

II b

GP

III

a

II

IIa

LMWH/UFH

Bivalirudin

Lepirudin

Dabigatran*

[Ximelagatran]

AZD0837

SCH530348

ADP

TxA2

Terutruban

E5555

GP

Ia/IIa GP Ib/IX/V

Ge

bh

ard

& B

ee

r 2

01

0

aFIXa aptamer

avWF aptamer

aFXI

The „DEAR“ Trials in AF

RE-LY ENGAGE AVERROES ARISTOTLE ROCKET-

Dabigatran Edoxaban Apixaban Apixaban Rivaroxaban

110/150 bid 30/60mg od 5mg bid 5mg bid 20mg od

INR 2-3 INR 2-3 ASA INR 2-3 INR 2-3

18,000pts 20,500 5,600 18,000 14,000

1 RF moderate R >/= 1RF 1 RF moderate-

CHADS 1: 32% CHADS >=2 „unsuitable“ high risk

CHADS 2: 35% „intolerant“ CHADS 2: 10%

CHADS 3: 33% CH >/=3: 90%

50% VK naive

W:open label Stopped premat DD S-INR; Neur. DD; Sham INR

S/SE S/SE S/SE S/SE S/SE

Event d:450 Time 24m Event d 36m Event d 448 Event d 405

>12m >14m

Published 3/2012 Published 4/2011 (Abstr)

Oral bioavailability ~6.5%

Plasma concentrations with biexponential

decline, mean terminal half-life 14–17h in

healthy volunteers independent of dose

NH2

N

NH

N

N

CH3

N

OO

O

N

O

O CH3

CH3

Dabigatran etexilate

Not metabolized by CYP450 enzymes, and does not affect the

metabolism of other drugs that utilize this system

80% renal excretion

Not affected by food

No specific antidote available

Contraindicated when creatinine clearance < 30 ml/min

May cause dyspepsia

No monitoring

Dabigatran etexilate

JACC 2010; 56:2067

150 Net difference -0.58%

110 Net difference -0.16%

Lancet 2010; 341:682

+5*

* +5 more cases/1,000 pts/year compared with W

* -5 less cases/1,000 pts/year

+2 +2

-5-4

-6

-6-4

-6*

The FDAs View

Rivaroxaban (Xarelto)

Oral and direct factor-Xa-Inhibitor

High oral bioavailability (80 - 100%)

Immediately effective: Cmax= 2 - 4 h (similar to NMH)

Halflife: 5 - 9h (elderly pts.: 11 - 13 h)

Dual mode of elimination

1/3 renal elimination

2/3 metabolized in the liver

Fixed dose – independent of food, BMI, gender, age

No monitoring

O.D.

Perzborn E et al. J Thromb Haemost 2005;3:514–521. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–880. Kubitza D et al. J Clin Pharmacol 2006;46:981–990. Kubitza D et al. Br J Clin Pharmacol 2007;63:469–476.Kubitza D et al. J Clin Pharmacol 2007;47:218–226. Kubitza D et al. Blood 2006;108:Abstract 905.

Rivaroxaban

N NO

NH

O

S

ClO

O

O

Rocket-AF: Primary Efficacy OutcomeStroke and non-CNS Embolism (OT)

Event Rates are per 100 patient-years

Based on Protocol Compliant on Treatment Population

No. at risk:

Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634

Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655

Warfarin

HR (95% CI): 0.79 (0.66, 0.96)

P-value Non-Inferiority: <0.001

Days from Randomization

Cu

mu

lati

ve e

ven

t ra

te (

%)

Rivaroxaban

Rivaroxaban Warfarin

Event

Rate 1.71 2.16

Net difference -0.45%

Rivaroxaban Warfarin

Event

Rate

Event

Rate

HR

(95% CI)P-value

On

TreatmentN= 14,143

1.70 2.150.79

(0.65,0.95)0.015

ITTN= 14,171

2.12 2.420.88

(0.74,1.03)0.117

Rivaroxaban

better

Warfarin

better

Primary Efficacy Outcome: Stroke and non-CNS Embolism

Event Rates are per 100 patient-years

Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations

30 R / 7,000=0.42%

Apixaban: A Factor Xa Inhibitor– Bicyclic pyrazole

– Highly selective for factor Xa inhibition: Ki = 0.08 nM

– Oral bioavailability: ≈ 50%

– Rapid absorption (Tmax 3h to 4h)

– No food effect

– Half-life: T1/2 ≈ 12 h

– Multiple elimination/excretion pathways: ~27% renal clearance

– No prodrug, no active metabolite

– No organ toxicity, LFT abnormalities, or QTc prolongation seen in studies

– B.I.D.

N

N

O

NH2

O N

N O

O

NEJM 2011; Febr 10

3.7%/y

1.6%/y

-2.1%

AVERROES2x5mg Apixaban vs Aspirin

NEJM 2011; Febr 10

1.2%/y

1.4%/y

Edoxaban and atrial fibrillationAHJ 2010; 160: 637

Individualized design; O.D.

Half dose, if

CCr 30-50ml,

<60kg,

Medi Verapamil

or Quinidine

ASA<100

Stop, if TRIPLE

The Forbidden Table:

Summary of Outcomes in %/year

D110 D150 Riva OT Riva ITT Apix War(-D) War(-R) ASA(-A)

RE-LY RE-LY ROCKET-AF AVER

Dabigatran Rivaroxaban Apixaban Warfarin

S/SE 1.53 1.11 1.71 2.12 1.6 1.69 2.16/2.42 3.7

ICB 0.23 0.30 0.49 0.20 0.74 0.74 0.3

Death 3.75 3.64 1.87 3.5 4.13 2.21 4.4

M‘Bleed 2.71 3.11 3.60 1.4 3.36 3.45 1.2

1) Otamixaban is an iv applicable substance after MI

2) Betrixabanis excreted unchanged in the bile and only minimal renal

excretion (<5%), will be suitable for pts with renal failure

3) YM150Phase II in AF

AZD 0837 (anti-IIa)

favorable in Phase II in AF

4) LY-517717

Rombouts in Thromb Haemost 2009; 101:552

4 Runner-ups?

1) Antiinflammatory and anti-atherosclerotic

effects of thrombin-inhibition

2) Thrombin activates protease activated

receptors (PAR 1-4) on plts and Lc

3) Thrombin activates thrombomodulin

4) Thrombin reduces endothelial NO

5) Thrombin stimulates smooths mm cell

proliferation (yet stabilizes the plaque)

JACC 2010; 56:2067

Anti-Thrombin-Effects Beyond Anticoagulation?

CH:68%Country Distribution of cTTR

Lancet 2010; 367:976

72% (Marko et al)

TTR subgroup analysis: time to primary outcome:D150 more effective if TTR is bad

Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation.This information is provided for medical education purposes only.

TTR = time in therapeutic range; cTTR = centre mean TTR

Wallentin L et al. Lancet 2010;376:975–83

Dabigatran 110 mg

Dabigatran 150 mg

WarfarinCum

ula

tive h

aza

rd r

atio

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1497 1450 1411 1144 649 274Dabigatran 110 mg1509 1469 1427 1164 699 283Dabigatran 150 mg1504 1445 1395 1094 640 242Warfarin

Number at risk

cTTR <57.1%

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1524 1477 1440 1169 783 3791526 1493 1453 1192 801 3941514 1476 1438 1175 752 351

cTTR 57.1–65.5%

Cum

ula

tive h

aza

rd r

atio

0.01

0.03

0.04

0.05

0.06

0

0.02

0

Follow-up (yrs)

0.5 1.0 1.5 2.0 2.5

1474 1456 1420 1142 760 370Dabigatran 110 mg1484 1419 1419 1153 761 369Dabigatran 150 mg1487 1458 1436 1150 755 359Warfarin

Number at risk

cTTR 65.5–72.6%

0.01

0.03

0.04

0.05

0.06

0

0.02

0 0.5 1.0 1.5 2.0 2.5

1482 1444 1405 1108 730 3471514 1487 1437 1135 750 3671509 1476 1440 1166 737 366

Follow-up (yrs)

cTTR >72.6%

21

D150

TTR subgroup analysis: time to major bleeding:More Bleeds in W if TTR is bad

Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation.This information is provided for medical education purposes only.

TTR = time in therapeutic range; cTTR = centre mean TTR

Wallentin L et al. Lancet 2010;376:975–83

Cum

ula

tive h

aza

rd r

atio

0.02

0.06

0.08

0.10

0.12

0

0.04

0 0.5 1.0 1.5 2.0 2.5

1497 1443 1398 1135 647 274Dabigatran 110 mg

1509 1448 1399 1135 680 276Dabigatran 150 mg

1504 1430 1371 1065 614 231Warfarin

Number at risk

cTTR <57.1%

0.02

0.06

0.08

0.10

0.12

0

0.04

0 0.5 1.0 1.5 2.0 2.5

1524 1465 1416 1139 753 362

1526 1467 1416 1160 774 377

1514 1460 1403 1140 729 333

cTTR 57.1–65.5%

Cum

ula

tive h

aza

rd r

atio

0.02

0.06

0.08

0.10

0.12

0

0.04

0

Follow-up (yrs)

0.5 1.0 1.5 2.0 2.5

1474 1445 1392 1108 736 364Dabigatran 110 mg

1484 1415 1372 1105 715 343Dabigatran 150 mg

1487 1445 1398 1121 725 344Warfarin

Number at risk

cTTR 65.5–72.6%

0.02

0.06

0.08

0.10

0.12

0

0.04

0 0.5 1.0 1.5 2.0 2.5

1482 1438 1385 1087 706 336

1514 1455 1399 1109 716 350

1509 1452 1411 1129 714 354

Follow-up (yrs)

cTTR >72.6%

Dabigatran 110 mg

Dabigatran 150 mg

Warfarin

22

W

NEJM 2003; 349:1019

„Why not compare INRs when things happen“

0.6 0.35

Ann Int Med 2011;154:1

Monitoring

aPTT

PTECT

TT

Thrombos Haemost 2010: 103:1116

Relevance of plasma concentrations?

No bleeding =baseline conc

Any bleeds (=major +minor): +20%

Major: +50%

Thrombos Haemost 2010: 103:1116

„…and if it is bleeding“

1) New anticoagulants targeting factor Xa and IIa have

been shown to be at least as effective and in some

instances superior in efficacy and side effects compared

to warfarin.

2) Individualized treatment options have emerged and

will further open new perspectives in the choice of dose

and substance according to the clinical situations.

Summary

Individualized Scenarios for the Future

1) Pts > 75-80y: Lower dose of D

2) Renal insufficiency:

Choose agent with hepatic

clearance or lower the dose.

3) High GI bleed risk: R?

4) Difficult compliance: O.D. ?

5) Excellent TTR: W?

6) CHADS>3: lower ds D, R, E?

7) „Unsuitable“ for Warfarin:

At lower CHADS Scores: A

TTR in the Warfarin ctr Group

ROCKET-AF (Rivaroxaban in AF): 58%

RE-LY (Dabigatran in AF): 68%

Recover (Dabigatran in DVT): 60%

Individualized dose recommendation based

on RE-LY and the new data analyses

Pradaxa in AF:

- 150 mg bid life-long

- pts > 80 yrs should be treated with 110 mg bid due to the increased bleeding risk

- 110 mg bid can be individually considered at discretion of physician when:

Thromboembolic risk is low AND bleeding risk is high e.g.

• age ≥75 yrs

• CHADS2 score ≥ 3

• moderate renal impairment

• concomitant treatment with a strong P-gp inhibitor

• GI bleed history

BLOOD 2010; 116:4390

„Safe(r) Anticoagulation“?Targeting FXI with Anti-Sense Oligonucleotides results abolishes

pathological thrombosis but has minor effects on haemostasis

TTR subgroup analysis: mean

TTR by country

34Disclaimer: Dabigatran etexilate is not approved for clinical use in stroke prevention in atrial fibrillation.This information is provided for medical education purposes only.

TTR = time in therapeutic range

Wallentin L et al. Lancet 2010;376:975–83

Mean T

TR (

%)

10

30

50

60

70

80

0

Country

20

40

Taiw

an

Mexic

o

Peru

Rom

ania

India

Colo

mbia

Russ

ia

Bra

zil

Chin

a

Kore

a

Gre

ece

Thaila

nd

Mala

ysi

a

Pola

nd

South

Afr

ica

Japan

Fra

nce

Slo

vakia

Port

ugal

Cze

ch R

epublic

Isra

el

Phili

ppin

es

Bulg

aria

Hungary

Hong K

ong

Turk

ey

Belg

ium

United S

tate

s

Aust

ria

Spain

Germ

any

Sw

itze

rland

Sin

gapore

Arg

entina

Neth

erlands

Norw

ay

Canada

United K

ingdom

Italy

Ukra

ine

Denm

ark

Aust

ralia

Fin

land

Sw

eden

4447 48

49 4953 53 54 55 55 56 56 56 57 58 58

60 60 61 62 64 64 64 64 64 65 65 66 66 66 67 68 6870 70 70 71 71 72 72 72

74 7477

Monitoring

aPTT

PTECT

TT

Thrombos Haemost 2010: 103:1116