View
216
Download
2
Category
Preview:
Citation preview
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
Recommended