C. Michael Gibson, M.S., M.D. Meeting The Unmet Needs in Chronic Anticoagulation.

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


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


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






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

C. Michael Gibson, M.S., M.D. Meeting The Unmet Needs in Chronic Anticoagulation.

Documents

Transcript of C. Michael Gibson, M.S., M.D. Meeting The Unmet Needs in Chronic Anticoagulation.