Thrombose-Prophylaxe und OAK 2011 - eft- · PDF fileRocket-AF: Rivaroxaban in Stroke und systemischer Embolisation Event Rates are per 100 patient-years Based on Protocol Compliant

Thrombose-Prophylaxe und OAK 2011

Scuol 4.9.11

0920-0945

JH Beer

Zukunft: Individualisierte und auf den Pat.

massgeschneiderte Antikoagulation

•Dabigatran-Pradaxa

•Rivaroxaban-Xarelto

•Apixaban-Eliquis

•Edoxaban

•Betrixaban

•Markoumar

•Heparine

•Kombinationen, u.a. mit

•Plättchenhemmern

„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

Weniger ICBs Outcome in %/Jahr

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

*Aristoteles: 0.24% vs 0.47%

Pharmakologische Eigenschaften neuerer Antikoagulantien

Annu Rev Med 2011; 62:41

Prophylaxe

Rivaroxaban in der orthopädischen

Chirurgie: 4 Studien zusammengefasst

Symptomatic VTE and

all-cause mortality

Major bleeding

1.3%

0.6%

0.2%0.4%

ARD=–0.8%

p<0.001

ARD=0.2%

p=0.076

13/6,200 24/6,18382/6,200 35/6,183

p-values analyzed using a Cox regression model; safety population, n=12,383

0

0.5

1.0

1.5

2.0

Incid

en

ce

(%)

Enoxaparin regimens

Rivaroxaban regimens

Primary populationfor analysis

Efficacy of the new OAC in orthopedic prophylaxis


Bleeding Risk of the new OAC in orthopedic prophylaxis


Kollege D. fragt, ob diese erfolgreiche orthopädische

Prophylaxe auf die multimorbiden medizinischen

Patienten übertragbar sei?

(Magellan)

Fall 2a

TVT

NEJM 2009; 361:2342

Re-Cover: Dabigatran

NEJM 2009; 361:2342

D: 2x150mg

NEJM 2009; 361:2342

NEJM 2010; 363:2495

NEJM 2010; 363:2495

TE and Rivaroxaban

NEJM 2010; 363:2495

Einstein Extension

Einstein-Extension

VHFli

JACC 2010; 56:2067

150 Net difference -0.58%

110 Net difference -0.16%

Rocket-AF: Rivaroxaban in Stroke und

systemischer Embolisation

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

Effektivität Rivaroxaban im VorhofflimmernStroke und nicht ZNS-Embolisation

Event Rates are per 100 patient-years

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

Blutungen beim Vorhofflimmern unter Rivaroxaban

NEJM 2011; e pub aug

NEJM 2011; Febr 10

3.7%/y

1.6%/y

-2.1%

NEJM 2011; Febr 10

1.2%/y

1.4%/y

NEJM 2011; aug 29th

2.13 vs 3.09%/y1.27 vs 1.60%/year

Pro 1000 Behandelte wird 6x stroke,

15x major bleeds und 8xTod verhindert

Das Dabigatran wird ja demnächst zugelassen in der

CH, es wurde in 2 Dosierungen zugelassen in Can, JPN,

in der höheren -2x150mg (und einer wesentlich tieferen

– 2x75mg) in den USA.

Gibt es Daten, die meiner Risikokategorie, meinem

Alter und meiner Co-Medikation gerecht werden?

Patienten und Hausarzt-Fragen

Clinical Chemistry, Vol.57, Nr.4,

April 2011

Neue Antikoagulantien: Die Fragen von

Patienten und ihren Aerzten

Zusammenfassung

1. Wirksamkeit: Mind gleich gut (in einigen Situationen besser)

2. ICB: Besser

3. Kein Lebersignal (bis jetzt)

4. Möglichkeit der Individualisierung / Wahl bzgl Risiko und Metabolismus

5. p.o.!

6. Nahrungsunabhängig? – weniger nahrungsabhängig!

7. Weniger Medikamenteninteraktionen

8. Monitorisierung? Patientenentscheid.

9. Antagonisierung? Aber kurze Halbwertszeit.

10.Compliance/Therapie-Unterbrüche?

11.Bridging?

12.Gut und sehr gut INR-Eingestellte zurückhaltend wechseln!

13. „Das Spiel dauert 90 min“

Kriterien für Auswahl: Niereninsuffizienz/ Schlechte Compliance:1xtägl/

Dyspepsie/ Medikamenteninteraktionen/Risikoprofil/

Aber ich bin doch perfekt eingestellt und „zu fast 100%“

im therapeutischen Bereich mit dem Marcoumar, ich

weiss, dass es fast nie blutet. Wie gross ist unter diesen

perfekten Bedingungen die Hirnschlag- und Hirn-

Blutungsgefahr wirklich?

Patienten Fragen

NEJM 2003; 349:1019

„Why not compare INRs when things happen“

0.6% 0.35%

Circ 2011; Oldgren ACC 3/2011

Risiko-Kategorie CHADSVASC und Outcome mit Dabigatran vs VKA

Circ 2011; 123: 2363 (mai 31)

Blutungen mit Dabigatran beim alten Menschen

Circ 2011; 123: 2363 (mai 31)

Hirnschlag und Blutungen mit Dabigatran beim alten Menschen

Circ 2011; 123: 2363 (mai 31)


Circ 2011; 123: 2363 (mai 31)

Blutungen mit Dabigatran in Komb mit Plättchenhemmern

BMJ 2008;336:614

No sig RR for MI

Benefit: MI 0.6% vs 1.0% ns

Risk: Major bleeds 3.9% vs 2.3% sig

ASA + C is not an alternative

Ann Int Med 2011;154:1

TTR in EINSTEIN

NEJM 2010; 363:2495

Stroke und TE-Ereignisse beim Vorhofflimmern unter Rivaroxaban

NEJM 2011; e pub aug

TTR Subgruppen-Analyse, geordnet nach Ländern

45Disclaimer: 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

Ich bin schlecht einstellbar mit meinem

Quickwert. Profitiere ich nun mehr oder weniger

von einer Umstellung auf die Neuen?

Patienten-Frage:

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


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%

47

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


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

48

W

Medikamenteninteraktionen

Specifics drugs Xarelto® Pradaxa®

With moderate CYP

inhibitors

acetaminophen, cyclosporine, erythromycin,

nifedipine, felodipine, midazolam, triazolam,

simvastatin, atorvastatin

No No

With strong CYP

inhibitors

Clarithromycine Yes, use

another

antibiotic

No

With P-gp inhibitors Quinidine,

Verapamil, Amiodarone,

Clopidogrel

No

No

no

Yes, do not combine

Yes, use with

caution

Yes, level increases

With strong CYP and

P-gp inhibitors

Ketoconazol (azole antimycotica)

Ritonavir (HIV protease inhibitors)

Avoid Avoid

With CYP inductors phenobarbital type inducers,

dexamethasone, phenytoin,

carbamazepine, and St. John’s wort

No, not

clinical

relevant

no

With strong CYP and

P-gp inductors

Rifampicil, Avoid Avoid

*Am J Manag Care 2009; 15 (6): e22-33

Wie steht es mit der Niereninsuffizienz?

Hausarzt-Frage:

Niereninsuffizienz: Halbwertszeit: Plasma

Konzentrations Kurven

S. Harder, J Clin Pharmacol, 24 May 2011, online

Dabigatran Rivaroxaban

after oral administration of dabigatran etexilate

(50 or 150 mg)

after administration of a single 10-mg dose of rivaroxaban

Dabi Rivarox

Stroke und SE: Dabigatran und Subgruppen?

NEJM 2009; 381: 1140

NE

JM

20

09

; 3

81

: 11

40

Bleeding x2

Dabi &Warfarin

Wie steht es mit dem Körpergewicht?

Hausarzt-Frage:

Rivaroxaban in VTE p OS:

Influence of body weight

• No relevant differences in

PK

– AUC unaffected

– Cmax increased by ~24% in

subjects ≤50 kg, not

considered clinically

relevant (inside bioequivalence

range)

• Close correlation between

PK and PD

• Fixed dosing

recommended in phase II

for patients of all weights

Time (hours)

Body weight ≤50 kg

Body weight 70–80 kg (normal weight)

Body weight >120 kg

0

20

40

60

80

100

120

140

160

180

0 2 4 6 8 10 12 14 16 18 20 22 24

Riv

aro

xab

an

pla

sm

a c

on

cen

trati

on

(µ

g/L

)

Rivaroxaban 10 mg

Kubitza et al., J Clin Pharmacol 2006;

Eriksson et al., J Thromb Haemost 2006; Circulation 2006;

Turpie et al., J Thromb Haemost 2005

Wie steht es mit dem Monitoring?

Hausarzt-Frage:

Monitoring

aPTT

PTECT

TT

Thrombos Haemost 2010: 103:1116

Relevance of plasma concentrations?

No bleeding =baseline conc

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

Major: +50%

Bedeutung der Compliance bei kurzen

Halbwertszeiten?

1x täglich oder 2x täglich?

Hausarzt-Frage:

Weniger ICBs Outcome in %/Jahr

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

*Aristoteles: 0.24% vs 0.47%

Poor Adherence to Once-Daily

Drugs is Common

21 clinical studies with 4,783 pts with 1 once daily

antihypertensive drug. Medication containers electronically record

the date and time of each opening:

At one year: 50% had stopped altogether

95% missed >1day/y

50% missed >1day/m

50% took drug holidays of >3 days

April-September sig worse than other months of year

Weekends are sig worse than weekdays

Evening takers worse than morning takers

Better execution correlates with long term compliance

BMJ 2008 336:1114

Pharmakokinetik?

Hausarzt-Frage:

…und wenns blutet?

Hausarzt-Frage:

Arch Int Med 2006; 166:853 Thrombos Haemost 2010; 103:1116

„…und wenns blutet?“

Case fatality of severe bleeds

was 9% in Warfarin and

similar to Ximelagatran

PCC 15ml/kg, 4FFP

Bridging –Procedere?

Hausarzt-Frage:

Brigding mit Dabigatran Douketis, 2011

Ich bin schlecht einstellbar mit meinem

Quickwert. Profitiere ich nun mehr oder weniger

von einer Umstellung auf die Neuen?

Patienten-Frage:

Rivaroxaban (Xarelto)

Oraler und direkter Factor-Xa-Inhibitor

Hohe orale Bioverfügbarkeit (80 - 100%)

Sofort aktiv: Cmax= 2 - 4 h (ähnlich LMWH)

Halflife: 5 - 9h (Aeltere Pat.: 11 - 13 h)

Dualer Eliminationsweg 1/3 renale Elimination

2/3 Metabolisierung durch die Leber

Fixe Dosis – unabhängig von Ernährung, Körpergewicht, Geschlecht und Alter (in

klinischen Studien)

Kein Monitoring erforderlich (spez anti-Xa assay). PT, aPTT werden

Medi-Interaktionen: CYP3A4-Hemmer erhöhen die Konzentration: Ketokonazol,

Ritonavir; p-gp Inhibitoren: Clarithromycin

CYP3A4 Induktoren erniedrigen die Konz.:Rifampicin Phenobarbital, Phenytoin,

Carbamacepin, Johanniskraut.

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

Aber ich bin doch perfekt eingestellt und zu fast 100% im

therapeutischen Bereich mit dem Marcoumar, ich weiss,

dass es fast nie blutet.

Patienten Fragen

Hausarzt Dr K. ruft mich an, er habe soeben einem 60 j.

Patienten mit Status 2J. nach TVT Xarelto 10mg für die

Reise nach S.F. (9h) und zurück mitgegeben. „Ob das in

meinem Sinne sei“? Der Pat möchte nicht spritzen und

doch „etwas tun“ und sein „Nachbar habe es doch

problemlos erhalten…“

Fall 2

A) Nein, keine Studien

B) Ja, ws wirksam und NW-arm, ähnliche T1/2 wie LMWH

C) Mechanische Prophylaxe hätte genügt

D) Wird nie Studien geben (?) Analogie-Schluss ziehen?

E) Warte mind auf Studien bei andern ortho-Eingriffen,

allg-chi Populationen, med. Patienten-Kollektiven*

*Magellan?

Fall 2

Halbwertszeit: Dabigatran Plasma Konz. Kurven

S. H

ard

er,

J C

lin P

harm

acol, 2

4 M

ay 2

011, onlin

e

after oral administration of dabigatran etexilate (50 or 150 mg)

The „DEAR“ Trials in AF

RE-LY ENGAGE AVERROES ARISTOTLE ROCKET-

Dabigatran Edoxaban Apixaban Apixaban Rivaroxaban

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

Published 3/2012 Published 4/2011 (Abstr)

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

>12m >14m

Bleeding

Comp EP.:TE, death

66j. Patientin mit TVT Oberschenkel links, unprovoziert,

schlecht einstellbar mit Markoumar (TTR<50%),

trotz häufiger INR, zT 2x/Woche, „will nicht mehr recht“.

Sie möchte nach 3 Monaten absetzen.

TTR?

Compliance?

Interaktionen, Medi?

Essen?

Co Diagnosen?

…

Risiko-Analyse: Blutungsgefahr, Rezidivgefahr?

Fall 3b

Time in Therapeutic Range (TTR)

INR Data (Rocket-AF Nov 2010)

INR range

Warfarin

Median (25th, 75th)

<1.5 2.7 (0.0 – 9.0)

1.5 to <1.8 7.9 (3.5 – 14.0)

1.8 to <2.0 9.1 (5.3 – 13.6)

2.0 to 3.0 57.8 (43.0 – 70.5)

>3.0 to 3.2 4.0 (1.9 – 6.5)

>3.2 to 5.0 7.9 (3.3 – 13.8)

>5.0 0.0 (0.0 – 0.5)

Based on Rosendaal method with all INR values included

Based on Safety Population

“Taken together, the key message appears that Dabigatran

has clear advantages over warfarin in terms of its efficacy

(with the 150mg dose) and safety (with the 110mg dose)

but that the net benefit is attenuated (and possibly nullified),

when there is good or excellent anticoagulation control with

Warfarin, as defined by a TTR of >72% “.

Douketis 2011

Kennen Sie Ihren TTR?

66j. Patientin mit TVT Oberschenkel links, unprovoziert

schlecht einstellbar mit Markoumar (TTR<50%),

trotz häufiger INR, zT 2x/Woche, „will nicht mehr“.

Nach einem Canada-Aufenthalt in Vancouver kommt sie

mit einer Packung Dabigatran (2x150 mg) zurück („sei ja

auch wirksam und brauche keinen Quick (Cousine in

Vancouver habe Vorhofflimmern…)“

Dabigatran?

(Pradaxa)

Rivaroxaban

(Xarelto)

Fall 3c

Hausarzt Dr A.K. fragt ob er einen Pat mit unprovozierter

TVT nach 1 Monat umstellen solle und dürfe: Der TTR

sei sehr mit >75% sehr gut und der HA ruft mich an,

Umstellung auf das Dabigatran ?

Pat habe von der neuen Medikation gehört und möchte umstellen. Wie?

Timing?

Wie lange?

Monitoring?

Gerinnungstests? Reversibilität?

Dialyse?

Bleeding?

Fall 3 (Frage 2011/12)

Monitoring

aPTT

PTECT

TT


Wenn die Thrombinzeit normal ist,

hats sicher kein Dabigatran an Bord

Monitoring

aPTT

PTECT

TT


Does Benefit/Risk Support Exploration of Higher

Doses of Dabigatran? The FDAs View

Oldgren ACC 3/2011

CHADS-VASc und Outcome mit Dabigatran vs VKA (Re-Ly-Analyse)

Circ 2011; 123: 2363 (mai 31)


Circ 2011; 123: 2363 (mai 31)


Circ 2011; 123: 2363 (mai 31)


Circ 2011; 123: 2363 (mai 31)

Blutungen mit Dabigatran in Komb mit Plättchenhemmern

Circ 2011; 123: 2363 (mai 31)

Obere oder Untere GI-Blutungen mit Dabigatran

Ann Int Med 2011;154:1

Die FDA Meinung

Half life

Specifics Xarelto® Pradaxa®

Healthy < 65 y 5 – 9 h (?) 10 h (?12-14)

Elderly 11 – 13 h 12 – 17 h

Moderate RI

(30 -49ml/min CrCl)

9 -10 h

Only small

AUC 30 -45% higher

18 h

Severe RI

(15 – 29ml/min CrCl)

11 – 13 h

Only small further increase

(10 mg, healthy)

27 h

Age has a moderate influence on half lifes.

Renal insufficiency (RI) has a low influence on the half life of Rivaroxaban,

but a strong influence on the half life of Dabigatran.

Half life: Dabigatran plasma

conc. curves


after oral administration of dabigatran etexilate (50 or 150 mg)

Half life: Rivaroxanban plasma

conc. curves


after the administration of a single 10-mg dose of rivaroxaban

Half life: plasma concentration

curves


Dabigatran Rivaroxaban

after oral administration of dabigatran etexilate

(50 or 150 mg)

after the administration of a single 10-mg dose of rivaroxaban

AUC variability, bioequivalence

range


Inter-individual 30 -40% Moderate to

high

Gender Not 30 -46% higher

in females

Bioequivalence

rangeAt steady state (3-4

days)

+40% / -30% + 25% / -20%

Therapeutic

window

wider narrower

Xarelto

Inter-individual differences lay within bioequivalence range for

Therapeutic window is wider

Pradaxa

50 mg bid too low (events), 300 bid too high (bleedings) (Petro trial)

Shallower dose–response

curve of Factor Xa suggests

wider safety margin• Thrombin only

activates clotting

over a narrow

concentration range;

Factor Xa functions

over a wider range.

– Dose–response

curves for DTIs and

direct Factor Xa

inhibitors would Esmon, ISTH 2005

0

20

40

60

80

100

120

0 50 100 150 200 250

Clo

ttin

g tim

e (

s)

Thrombin

Factor Xa

Enzyme dilution

These findings suggest that maintaining the appropriate dose

range for Factor Xa inhibitors may be easier than for DTIs

Phase II studies in VTE p OS:Low correlation of dose with efficacy,

all doses better than Enoxaparin

Eriksson et al. Circulation 2006;114:2374–2381.

40

30

20

10

0

0 5 10 20 30 40

Incid

ence –

effic

acy (

%)

Rivaroxaban (mg total daily dose)Enoxaparin

40 mg od

Shallow dose efficacy curve

En

ox

ap

arin

Riv

aro

xa

ba

n

Wide therapeutic window

Incidence of DVT, PE, and all-cause mortality

p=0.0852

Phase II studies in VTE p OS:Low correlation of dose with major

bleeding

Eriksson et al. Circulation 2006;114:2374–2381.

30

20

10

0

0 5 10 20 30 40Rivaroxaban (mg total daily dose)

Enoxaparin

40 mg od

Incid

en

ce

–sa

fety

(%

)

p=0.039

Major, post-operative bleeding

Shallow curve = low correlation

- > Wide safety margin

AUC vs doses used in Rocket

AF / Re-Ly


AUC at

steady state

20 mg = 3164

µg*h/L

15 mg* = 3249

µg*h/L

150 mg = 36%

higher than 110

mg

Plasma level

differences

between

doses

No difference Difference

outside of

bioequivalence(+25%, -20%)

Peak vs

trough level

(5th to 95th perc.)

20 mg od

250 vs 44 ng/ml (160-360) vs (5 -95)

ng/ml

150 mg bid

184 vs 90 ng/ml(64-443) vs (31-225)

ng/ml

Measured AUC values in Rocket confirm dose reduction in moderate RI patients.

Two Pradaxa doses clearly different (outside bioequivalence range),

difference of 36% gives significantly different outcomes.

Significant correlation between trough level and bleeding with Pradaxa

* Patients with CrCl of 30 -49 ml

99th percentile

95th percentile

75th percentileMedian

25th percentile

5th percentile

1st percentile

Key:

Phase III patients (10 mg, od)

10

12

14

16

18

20

22

24

26

28

30

32

Baseline

Predicted Observed

Trough

Predicted Observed

Peak

Predicted Observed

Pro

thro

mb

in t

ime

(s)

Baseline: pre-surgery

Trough: 20–28 h post-dosing

Peak: 2–4 h post-dosing

Predictable PK/PD in phase

III studies

Bioavailability


Healthy subjects 80-100 % 3-7%

pH dependent No Yes, plasma level

reductions with PPIs

Food dependent? 10 mg no,

15-20 mg with food

(39% AUC incr.)

No, but with food 2h

longer to Cmax

Dyspesia stronger

without food

Linear up take? No, ceiling >50 mg Yes, up to 600 mg

Greater variability in bioavailability with Pradaxa

Metabolism / elimination


Prodrug No, active substance Yes, hydrolized by

esterases

Liver, CYP 450 system 66% (CYP 3A4 u.a.) No hepatic

metabolization

Liver, glucuronidation Not observed Yes, into 4 different

substances

Liver interaction Not an inducer or a

inhibitor of the CYP

system

Not an inducer or a

inhibitor of the CYP

system

Kidney 33% active substance,

33% inactive metabolites

>85% active substance

Xarelto

dual mode of elimination

no surprises due to polymorphism in prodrug metabolization

Renal elimination only modest -> less accumulation in RI

Relevant interactions with other drugs

Specifics drugs Xarelto® Pradaxa®

With moderate CYP

inhibitors

acetaminophen, cyclosporine, erythromycin,

nifedipine, felodipine, midazolam, triazolam,

simvastatin, atorvastatin

No No

With strong CYP

inhibitors

Clarithromycine Yes, use

another

antibiotic

No

With P-gp inhibitors Quinidine,

Verapamil, Amiodarone,

Clopidogrel

No

No

no

Yes, do not combine

Yes, use with

caution

Yes, level increases

With strong CYP and

P-gp inhibitors

Ketoconazol (azole antimycotica)

Ritonavir (HIV protease inhibitors)

Avoid Avoid

With CYP inductors phenobarbital type inducers,

dexamethasone, phenytoin,

carbamazepine, and St. John’s wort

No, not

clinical

relevant

no

With strong CYP and

P-gp inductors

Rifampicin, Avoid Avoid

*Am J Manag Care 2009; 15 (6): e22-33

Daily intake


Doses Once daily

20 mg pill

Small: 6 mm

Twice daily

150 mg capsules

Large: 18 mm

Special precautions No Sensitive to moisture (keep in

blister, no ‚week pill box‘

packing)

Manipulations Splitting possible No breaking, chewing of

capsule, swallow as a whole

Bioavailability is increased by

75% with granules only

Once daily dosing found to have 50% better compliance than twice daily*

Small pill preferable, large capsules often a problem for the elderly

Preparing week pill boxes and graining possible with Xarelto

* Am J Manag Care 2009; 15 (6): e22-33

Rivaroxaban dose-dependently inhibits

peak thrombin generation up to 24 hours

Healthy volunteers

ETP, endogenous thrombin potential.

0 2 4 6 8 10 12 14 16 18 20

ET

P-p

eak (

co

llag

en

)

0

20

40

60

80

100

Time (hours)

0 2 4 6 8 10 12 14 16 18 20 22 24

ET

P-p

eak (

tissu

e f

acto

r)

0

20

40

60

80

100

Time (hours)

30 mg rivaroxaban (n = 8)

5 mg rivaroxaban (n = 8)

Placebo (n = 8)

Intrinsic coagulation pathwayExtrinsic coagulation pathway

Adapted from Harder S et al. Blood 2003;102:A3003.

22 24

One dose for all patients?


Age (>18y) No age limit (97y max)

Low influence so fare

Further analysis needed

71y (+/-8.8)

Bleeding pattern

significantly different in

age goups

Weight Low influence so far

VTEp OS

>100 kg, trend to VKA

better (110 significantly

better than 150)

Co-medications More bleeding with

ASS, but similar in both

arms

Most other common

drugs have low

influence

More bleeding with

ASS, but similar in both

arms, use ASS with

caution

PPI, Amiodarone,

Quinidine influence

plasma conc, trend to

worser outcome

*Am J Manag Care 2009; 15 (6): e22-33

Dose adjustements in renal insufficiency


>50 – 80 ml / Cr Cl No, 20 mg; od No, 150 mg; bid

30 -49 ml / Cr Cl Yes, SPAF 15 mg; od No, 150 mg; bid

15 – 29 ml CrCL 15 mg (very few

patients)

VTE p OS (10 mg) use

with caution

75 mg only in US,

Contra-indicated in

VTE p OS

< 15 ml CrCl Not recommended Contra-indicated

Dose adjustements in ROCKET AF by intention to get homegeneous

AUC down to 30 ml CrCl. All patient can be pooled.

Unclear situation with Pradaxa, different dose recommendations in US

(75 mg), CAN and EU likely

75 mg Pradaxa dose not studied

Age and renal function – only

moderate influence

• Data are consistent with

phase I results

• Fixed-dose rivaroxaban can

be administered to patients:

– With mild-to-moderate renal

impairment

– Irrespective of age

• Phase III studies

– Enrolled patients with no upper

age limit

– Include patients with moderate

renal impairment

Mueck et al., Blood 2006

Dose intake forgotten


Same day Take missed tablet,

any time up to 7 pm

Take missed capsule,

not if <6 h to next dose

Never take two

capsules

Yesterday Take your daily dose,

Any time up to 7 pm

Take missed capsule,

never take two at once,

take it only if >6h to next

dose

24h plasma level after

last dose

ca 42 ng/ml ca 30 ng/ml

48h plasma level after

last dose

Under detection limit Under detection limit

Overdose / intoxication


Antidote Not yet available Not yet available

Plasma concentration

saturation effect

Yes, ceiling effect>50 mg little further conc.

increase

NoLinear increase 10 – 600 mg

Counter measure

No bleeding

Active charcoal (up to 8h after intake)

Increase diuresis

Active charcoal(up to 2h after intake)

Increase diuresis

Counter measure

bleeding

Little experience yet,

try similar procedure as

with bleedings under

LMWH

Hemodialysis

(68% in 4h)

Short half lifes of both drugs reduce risk further, No acute toxic effect of both drugs

Ceiling effect with Xarelto limits plasma concentration level

Little experience with bleeding complications under high drug

plasma concentration, but FVIIa and PCC work in animal models

Quantification


Lab tests Chromogenic anti Xa

assay in place

(RivaMoS)Soon commercially available

Peak and trough levels can be

measured accurately

Hemoclot® Thrombin

Inhibitor assay (same as

for Hirudin, argatroban) Hyphen, commercially

available

Point of care Quick test available

(with Neoplastin)

Only suitable to

measure peak levels

(2-4h after intake)

aPPT,ACT; but relative

flat curve, mainly to

confirm intake (peak

levels)

or TT (sensitive), but not

so common

Xarelto can now be quantified on a fully automatable common lab assay

Mean plasma concentration ranges of the drugs are know, but

clinical significance of specific level unknown.

Time of intake essential when comparing plasma concentrations

Influence of drug on lab tests


Coagulation tests:

Strong influence

(always also dependent on

reagents and coagumeter)

Anti Xa Heparin tests Thrombin time

Hemoclot Thrombin inhibitor test

(Hirudin, Argatroban),

ECT,

Moderate influence Quick: increase in s, decrease in %

aPPT: increase in s,

FII, FV, FVII, FVIII, FIX, FX assays

(PTor aPPT based) apparent factors

level will be decreased

aPPT: 2x at peak, increase in s,

ACT, flat curve

No influence D-Dimers, Fibrinogen, Thrombin

Time, FXIII and Antithrombin

Quick: little effect

D-Dimers, Fibrinogen,

Platelet tests Not influenced No?

Point of care Thrombelastograms minor influence

INR will be influenced

Other (clincial

chemistry)

Not known, not observed yet ?

Baseline Demographics

Topic specifics Xarelto 20 mg Pradaxa 150 mg

Rocket AF Re-Ly

Age years 73 71.5

>75 years 43.80%

Females 40% 36.80%

Race white 83% 70.20%

Asian 13%

Region North America 19% 36%

Latin America 13% 5.30%

Asia Pacific 15% 15.40%

Central EU 38% 11.60%

Western EU 15% 25.60%

VKA naive 37.70% 49.80%

never used 31.40%

CrCL median 67 ml 67.9 ml

31- 50 ml 21%

50-80 ml 47%

>80 ml 32%

AF type persistent/permanent 81% 67.40%

paroxysmal 18% 32.60%

Patient medical condition and medication


Rocket AF Re-Ly

CHADS2 score 0 0 2.40%

1 0.01% 29.90%

2 13% 35.20%

>= 3 87% 32.60%

mean 3.5 2.1

Co-morbidities Stroke,TIA 55.00% 20%

Stroke all 34.30%

TIA 22%

non CNS SE 4%

CHF 63% 31.80%

Diabetes mellitus 40% 23.10%

Hypertension 90% 79%

Prior MI 16.6% 16.90%

Patient medical condition and medication – ctd.


Rocket AF Re-Ly

Co-Medication ASA during study 35% (relevant)39% (any time)

19.6% (always)

ASA prior study 37% 38.50%

Clopidogrel prior study 2.3% 5.50%

Clopidogrel during

study3.4% 2.20%

ASS & Clopidogrel prior

study3.50%

ASS & Clopidogrel

during study1.10%

Patient flow


Rocket AF Re-Ly

Number of

patientsScreeing 17'232 20'382

total ITT population 14'264 18'113

total Safety population 14'236 18'040

total Per-protocol

population14'054 17'630

on study drug 7'008 6'059

on Warfarin 7'046 5'998

Completed on study

medication4'591 4'627

stopped study

medication, but

completed study

2520 (35.4%) 1197 (19.8%)

stopped on warfarin 2468 (34,6%) 907 (15%)

Difference in early

discontinuation vs

warfarin

no difference

about 4.8% higher in

the DE arm than

warfarin

NEJM 2003; 349:1019

0.6 0.35

Neue Antikoagulantien:

Heutige Ziele:

1. Update 7. Monitoring

2. Off-label 8. 3.Welt

3. Compliance vs TTR 9. Zulassungen

4. Bleeds: ICB and GI 10. Kosten

5. 80+ 11. Triple Therapie m PH

6. CCreat 12. Individuelles Massschneidern

ZusammenfassungDer Zug hat die Station verlassen

Individualisierte Therapien möglich

Effektivere Antikoagulantien sind bereits zugelassen

Weitere werden folgen. Patienten und Aerzte haben schon entschieden.

Bedeutung der

Compliance bei

kurzen

Halbwertszeiten

1x/d oder 2x/d?

Markoumar

und…ASA etc?

Circ 2011; 123: 2363 (mai 31)

Obere oder Untere GI-Blutungen mit Dabigatran

Pat mit Vorhofflimmern: Welches ist mein alljährliches

Risiko, eine intracerebrale Blutung unter diesen

Antikoagulantien zu erleiden?

Patienten Fragen

Anti IIa und anti Xa vs VKAHeutige Ziele: Einsatz beim Vorhofflimmern

(Prophylaxe und Therapie der TE)1. Der alte Mann und das Meer (von neuen Medikamenten)

2. Tod, TE vs Blutungen, ICB

3. Kombinationen mit P-Hemmern

4. NW, Hepatotoxizität

5. Nahrung, Medikamenteninteraktionen

6. Monitoring?

7. Antagonisierung/Procedere bei Blutungen

8. Neueste Daten

9. TTR des INR als allg Qualitätsmarker –

10.T ½, Dosis-Intervall, und Compliance

11.Langzeiteffekt und Sicherheit

12.Preis

13.Individualisierung der Therapie

Hausarzt Dr S. (ein ehemaliger AA) ruft mich an, er möchte die

Austrittsmedikation einer 76j. chirurgischen Pat. mit mir besprechen:

Staus nach Hüft TP vor 1 Woche, DM II, CCreat 40ml/min, Status nach

stroke, kompensierte Herzinsuffizienz (EF 40%), hypertensiv,

intermittierendes VHFli, 80kg Medikation (15) Cordarone 200 mg: 1-0-0

Sortis 20mg 1-0-0

Aspirin 100mg 1-0-0

Enatec 20 mg 1-0-0

Xarelto 10mg 1-0-0

Glucophage 500 1-1-1

Fraxiparin 0.8ml 0-0-1

Pantozol 40mg 1-0-0

Brufen 600mg 1-1-1

Anxiolit 15 mg 0-0-1

Remeron30 mg 0-0-1

KCl Drg 1-1-1

Diflucan 50 mg 1-0-0 für 5 Tage

Klazid 500 1-0-1 für 3 Tage

Novalgin 500mg iR 2-2-2

Fall 1: Frau, 76j Risiko-Analyse und Umstellung?

Was beanstanden Sie?

Scientific American 2011

Fall 1: Die Limiten der Intelligenz

Hausarzt Dr S. (ein ehemaliger AA) ruft mich an, er möchte die

Austrittsmedikation einer 76j. Patientin mit mir besprechen:

Staus nach Hüft TP vor 1 Woche, DM II, CCreat 40ml/min, Status nach TIA,

kompensierte Herzinsuffizienz (EF 40%),hypertensiv, intermittierendes

VHFli

Medikation:Cordarone 200 mg: 1-0-0

Sortis 20mg 1-0-0

Aspirin 100mg 1-0-0 CHADS Vasc=5

Enatec 20 mg 1-0-0

Xarelto 10mg 1-0-0

Glucophage 500 1-1-1

Fraxiparin 0.8ml 0-0-1

Pantozol 40mg 1-0-0

Brufen 600mg 1-1-1

Anxiolit 15 mg 0-0-1

Remeron30 mg 0-0-1

KCl Drg 1-1-1

Diflucan 50 mg 1-0-0 für 5 Tage

Klazid 500mg 1-0-1 für 3 Tage

Novalgin 500mg iR 2-2-2

Fall 1: Frau, 76j

Welches ist mein alljährliches Risiko, einen Hirnschlag

oder eine Embolie zu erleiden?

Patienten Fragen

Risk Assessment and Stratification

CHEST 2010; 137:263

8 Points**************

Risk Assessment and Stratification: CHADS-VASc

CHEST 2010; 137:263

Ca 10%

Welches ist mein alljährliches Risiko, eine schwere

Blutung zu erleiden?

Patienten Fragen

Def Major Bleeds: Any bleed requiring hospitalisation, decrease of Hb >2g% or transfusion

CHEST 2010/3/18 online

Our Patient:4-5 points

*

*

**

Major Bleeds gem HAS-BLED Score, berechnet aus der SPORTIF Population

JACC 2011;57: 173

Wie ist denn das Nutzen-Risikoverhältnis bei den

Neueren AK resp. auf welches sollte ich denn

umstellen?

Patienten Fragen

„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

Kollateral-Nutzen oder –Schaden der

Thrombinhemmer?

Platelet activation

Vasoconstriction

Growth Factor (SMC) ?

Inflammatory Mediator

Thombomodulin/Protein C ?

Infection control?

Orale Bioverfügbarkeit ~6.5%

Mittlere Halbwertszeit 14–17h in

Gesunden unabhängig von der Dosis

NH2

N

NH

N

N

CH3

N

OO

O

N

O

O CH3

CH3

Dabigatran etexilate

Nicht metabolisiert durch CYP450 Enzyme, und interferiert nicht mit dem

Metabolismus anderer Medi, die dieses System brauchen.

Medi-Interferenzen; GP1 (Cordarone +50%) Rifampicin, Tenofivir,

Clarithromycin, Verapamil und Chinidin

80% renale Ausscheidung

Keine Interferenz mit Nahrungsmitteln

Bisher kein spezifisches Antidot verfügbar ****

Kontraindiziert bei CCr < 30 ml/min

Dyspepsie in 5%

Dabigatran etexilate

Apixaban: Ein Faktor 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

N

N

O

NH2

O N

N O

O

Documents

Thrombose-Prophylaxe und OAK 2011 - eft- · PDF fileRocket-AF: Rivaroxaban in Stroke und systemischer Embolisation Event Rates are per 100 patient-years Based on Protocol Compliant