C. Michael Gibson, M.S., M.D.C. Michael Gibson, M.S., M.D.
Meeting The Unmet Needs in Meeting The Unmet Needs in Chronic AnticoagulationChronic Anticoagulation
PCI Cure: Death / MI Remain High at One Year PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet TherapyDespite PCI & Dual Antiplatelet Therapy
PCI Cure: Death / MI Remain High at One Year PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet TherapyDespite PCI & Dual Antiplatelet Therapy
Lewis BS, et al. Am Heart J. 2005;150:1177-1184.
0.20
0.15
0.10
0.05
0.0Cu
mu
lati
ve H
azar
d R
ates
Dea
th /
MI
0 100 200 300Days of Follow-up
<48 hrs after rand
RR:0.53 (0.27-1.06)
Denotes medianTime to PCI
0.20
0.15
0.10
0.05
0.0
0 100 200 300Days of Follow-up
PCI ≥ 48 hrs from rand and during initial hosp
RR:0.72 (0.51-1.01)
ASA + Clopidogrel
ASA
PCI after hospitaldischarge
0.20
0.15
0.10
0.05
0.0
0 100 200 300Days of Follow-up
RR:0.70 (0.48-1.02)
ASA + Clopidogrel
ASA + Clopidogrel
ASA
ASAASA
Thrombus & Complex Lesion Remains One Month After STEMI
Thrombus & Complex Lesion Remains One Month After STEMI
Van Belle et al. Van Belle et al. Circulation. 1998;97:26-33.Circulation. 1998;97:26-33.
% T
hrom
bus
on
Ang
iosc
opy
% T
hrom
bus
on
Ang
iosc
opy
< 8 Days
(n=18)
< 8 Days
(n=18)
8 < &
< 10 Days
(n=10)
8 < &
< 10 Days
(n=10)
> 15 Days
(n=14)
> 15 Days
(n=14)
10 < &
< 15 Days
(n=14)
10 < &
< 15 Days
(n=14)
83%
70% 71%79%
0%
20%
40%
60%
80%
100%
Days after lysis or medical therapyDays after lysis or medical therapy
• Angioscopic findings suggestive of plaque instability are extremely frequent (75% to 80% of the study population) as is the presence of clot even in the absence of clinical symptoms.
• Only 16% of clot seen on angio
Takano M, et al. Eur Heart J. 2006;27:2189-2195.Takano M, et al. Eur Heart J. 2006;27:2189-2195.
Angioscopy Follow-up 6 Months Angioscopy Follow-up 6 Months After SES or BMS ImplantationAfter SES or BMS ImplantationAngioscopy Follow-up 6 Months Angioscopy Follow-up 6 Months After SES or BMS ImplantationAfter SES or BMS Implantation
PP=.031=.031
Fre
qu
enc
y o
f P
ersi
sten
ce
Fre
qu
enc
y o
f P
ersi
sten
ce
of
Th
rom
bu
s (%
)o
f T
hro
mb
us
(%)
**PP<.001 compared<.001 comparedwith the correspondingwith the correspondingsegment in the BMS.segment in the BMS.
EdgeEdge
BodyBody
OverlappingOverlappingSegmentSegment
n=21 n=33 n=12n=21 n=33 n=12SESSES
n=28 n=33 n=5n=28 n=33 n=5BMSBMS
**
****
PP<.0005<.0005 PP<.05<.05
PP<.001<.001
PP=.63=.63 PP=.80=.80
PP=.70=.70
Ste
nt
Co
vera
ge
Gra
de
Ste
nt
Co
vera
ge
Gra
de
00
0.50.5
11
1.51.5
22
2.52.5
n=7n=7SESSES
n=7n=7BMSBMS
00
2020
4040
6060
8080
100100
(N=46, 66 lesions: 33 SES, 33 BMS)(N=46, 66 lesions: 33 SES, 33 BMS)
>80%>80%
Grade 0Grade 0No neointimaNo neointima
Grade 1Grade 1Thin neointimaThin neointima
Grade 2Grade 2Full neointimaFull neointima
VisibleVisibleThrombusThrombus
Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy
Incidence of LV Mural Thrombus in the Era of Modern Reperfusion Therapy
• Series from 1997-2002Series from 1997-2002
• Among first anterior Among first anterior STEMI patients echoed STEMI patients echoed within 72 hours LV clot within 72 hours LV clot was seen in was seen in 23.5%.23.5%. (36/153)(36/153)
Porter A et al. Coron Artery Dis. 2005 Aug;16(5):275-9 Porter A et al. Coron Artery Dis. 2005 Aug;16(5):275-9
* STEMI pts managed with lytic or medical mgt* STEMI pts managed with lytic or medical mgt
Confidential. Do Not Distribute. Prasugrel is not FDA indicated for use.
Thrombin
Positive Feedback Loops
“Amplification”“Burst”“Cascade”“Activation”
Meta Analysis of AnticoagulationMeta Analysis of Anticoagulation
Rates of Recurrent MI
Rothberg et al. Ann. Int. Med. 2005;143:241-250Rothberg et al. Ann. Int. Med. 2005;143:241-250
ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common
ASPECT II: Coumadin is Efficacious in ACS, But Discontinuation is Common
999 Pts within 8 wks of UA or Acute MI999 Pts within 8 wks of UA or Acute MIRx Rx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg: ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg
Dea
th,M
I,C
VA
1 1 21 1 1
58
15
0
10
20
30
ASA Coumadin Combo
%
Major BleedTranfusionMinor Bleed
van Es et al van Es et al Lancet 360Lancet 360:109,2002:109,2002
Rate ofRate ofDiscontinuationDiscontinuation
10% 19% 20%
EfficacyEfficacy SafetySafety
OASIS 2: Impact of Anticoagulation OASIS 2: Impact of Anticoagulation DiscontinuationDiscontinuation
OASIS 2: Impact of Anticoagulation OASIS 2: Impact of Anticoagulation DiscontinuationDiscontinuation
8.98.9
16.516.5
6.16.1
11.911.9
18.518.5
99
21.321.3
7.87.8
00
55
1010
1515
2020
% P
ts%
Pts
P=0.33P=0.33
CVD,MI,CVACVD,MI,CVA CVD, MI, CVA, Rehosp UACVD, MI, CVA, Rehosp UA
Compliance:Compliance: Good Good BadBad GoodGood BadBad(% on Oral AC)(% on Oral AC) >>70 %70 % < 70% < 70% >> 70% 70% < 70% < 70%
P=0.02P=0.02 P=0.005P=0.005 P=0.16P=0.16
Std RxStd Rx
Oral A/C + ASAOral A/C + ASA
OASIS Inv OASIS Inv JACCJACC 37:475,2001 37:475,2001
16.3%16.3%
12.7%12.7%
0%0%
5%5%
10%10%
15%15%
20%20%
PlaceboPlacebo Pooled XimelagatranPooled Ximelagatran
n=1,245n=1,245 n=638n=638
p=0.03p=0.03
% D
eath
/MI/
Rec
urr
ent
% D
eath
/MI/
Rec
urr
ent
Isch
emia
Isch
emia
ESTEEM: Primary EndpointESTEEM: Primary EndpointESTEEM: Primary EndpointESTEEM: Primary Endpoint
Death/MI/Severe Recurrent IschemiaDeath/MI/Severe Recurrent Ischemia
• The primary endpoint The primary endpoint was lower for pooled was lower for pooled ximelagatran compared ximelagatran compared with placebo (12.7% vs with placebo (12.7% vs 16.3%, HR 0.76, 16.3%, HR 0.76, p=0.03)p=0.03)
• Ximelagatran Dc’d in Ximelagatran Dc’d in 7% of pts due to LFT 7% of pts due to LFT abnormalitiesabnormalities
Oral direct thrombin inhibitor (IIa), no coagulation monitoring is Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMIrequired, fixed dose, eval in STEMI or non-STEMI
XIXI XIaXIa
IXIX IXaIXa
XaXa
IIII IIa (Thrombin)IIa (Thrombin)
FibrinogenFibrinogen FibrinFibrin
VIIIaVIIIa
VaVa
VIIa + TFVIIa + TF VIIVII
TF (Tissue Factor)TF (Tissue Factor)
XX
Factor Xa Inhibition: At The Intersection of the Intrinsic and Extrinsic Pathways
Factor Xa Inhibition: At The Intersection of the Intrinsic and Extrinsic Pathways
Extrinsic PathwayExtrinsic Pathway
Intrinsic PathwayIntrinsic Pathway
If either the Intrinsic If either the Intrinsic oror Extrinsic Extrinsic pathway is activated, Factor Xa pathway is activated, Factor Xa inhbitors inhbitors block the final common block the final common coagulation pathway to form coagulation pathway to form thrombin by blocking Factor XAthrombin by blocking Factor XA
Meeting the Unmet Needs in Long Term Anticoagulation in ACS
Meeting the Unmet Needs in Long Term Anticoagulation in ACS
• SafeSafe
• EffectiveEffective
• Ease of useEase of use
No monitoringNo monitoring
Unaffected by dietUnaffected by diet
New AntithrombinsNew Antithrombins
TFPI (tifacogin)
FondaparinuxIdraparinux
RivaroxabanApixabanLY517717YM150DU-176bPRT-054021
XimelagatranDabigatran
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
Time (minutes)Time (minutes)
00 1010 2020 3030 4040 5050
Th
rom
bin
co
nce
ntr
atio
n (
nM
)T
hro
mb
in c
on
cen
trat
ion
(n
M)
00
2020
4040
6060
8080
100100
120120
Control Control
5 nM Rivaroxaban5 nM Rivaroxaban
10 nM Rivaroxaban10 nM Rivaroxaban
20 nM Rivaroxaban20 nM Rivaroxaban
50 nM Rivaroxaban50 nM Rivaroxaban
80 nM Rivaroxaban80 nM Rivaroxaban
100 nM Rivaroxaban100 nM Rivaroxaban
Rivaroxaban Inhibits Thrombin Rivaroxaban Inhibits Thrombin GenerationGeneration
Rivaroxaban Inhibits Thrombin Rivaroxaban Inhibits Thrombin GenerationGeneration
• In vitroIn vitro: platelet-rich human plasma activated by diluted tissue factor: platelet-rich human plasma activated by diluted tissue factor
Gerotziafas & SamamaGerotziafas & Samama.. ICT 2004, Ljubljana, Slovenia, ISTH 2005, Sydney, Australia ICT 2004, Ljubljana, Slovenia, ISTH 2005, Sydney, Australia
Oral Factor Xa Inhibitors In Clinical Development
Oral Factor Xa Inhibitors In Clinical Development
Rivaroxaban (Bayer)Rivaroxaban (Bayer) Phase IIb Phase IIb Phase III Phase III
Apixaban (BMS)Apixaban (BMS) Phase III Phase III
YM150 (Astellas)YM150 (Astellas) Phase IIb Phase IIb
DU-176b (Daiichi)DU-176b (Daiichi) Phase IIb Phase IIb
LY517717 (Lilly)LY517717 (Lilly) Phase IIb Phase IIb
813893 (GSK)813893 (GSK) Phase I/II Phase I/II
PRT054021(Portola) Phase IIPRT054021(Portola) Phase II
Factor Xa Inhibitors in DevelopmentFactor Xa Inhibitors in Development
IndicationIndication VTE prevention*VTE prevention* VTE treatmentVTE treatment Stroke Stroke prevention in prevention in
patients with AFpatients with AF
Other?Other?
IdraparinuxIdraparinux –– Phase III results Phase III results expected soonexpected soon
Phase III haltedPhase III halted ––
Rivaroxaban Rivaroxaban Phase IIIPhase III Phase IIIPhase III Phase IIIPhase III ACS Phase IIACS Phase II
LY517717LY517717 Phase IIb Phase IIb completedcompleted
–– –– ––
YM150YM150 Phase IIa Phase IIa completedcompleted
–– PlannedPlanned ––
DU-176bDU-176b Phase IIa Phase IIa completedcompleted
–– PlannedPlanned ACS plannedACS planned
ApixabanApixaban Phase IIb Phase IIb completed; planned completed; planned in cancer patientsin cancer patients
Phase II Phase II underwayunderway
–– Post-ACS plannedPost-ACS planned
PRT-054021PRT-054021 Phase II plannedPhase II planned PlannedPlanned PlannedPlanned Secondary Secondary prevention of stroke prevention of stroke
and MI plannedand MI planned
*Prevention of VTE after major orthopaedic surgery, unless indicated