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Meeting The Unmet Needs in Chronic Anticoagulation. C. Michael Gibson, M.S., M.D. PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy. PCI after hospital discharge. PCI ≥ 48 hrs from rand and during initial hosp . <48 hrs after rand. 0.20. 0.20. 0.20.

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pci cure death mi remain high at one year despite pci dual antiplatelet therapy
PCI Cure: Death / MI Remain High at One Year Despite PCI & Dual Antiplatelet Therapy

PCI after hospital

discharge

PCI ≥ 48 hrs from rand and during initial hosp

<48 hrs after rand

0.20

0.20

0.20

Denotes median

Time to PCI

ASA

ASA

0.15

0.15

0.15

ASA

0.10

0.10

0.10

Cumulative Hazard Rates Death / MI

ASA + Clopidogrel

ASA + Clopidogrel

0.05

0.05

0.05

ASA + Clopidogrel

RR:0.72 (0.51-1.01)

RR:0.53 (0.27-1.06)

RR:0.70 (0.48-1.02)

0.0

0.0

0.0

0

100

200

300

0

100

200

300

0

100

200

300

Days of Follow-up

Days of Follow-up

Days of Follow-up

Lewis BS, et al. Am Heart J. 2005;150:1177-1184.

thrombus complex lesion remains one month after stemi
Thrombus & Complex Lesion Remains One Month After STEMI
  • 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

100%

83%

% Thrombus on Angioscopy

79%

80%

71%

70%

60%

40%

20%

0%

< 8 Days

(n=18)

8 < &

< 10 Days

(n=10)

10 < &

< 15 Days

(n=14)

> 15 Days

(n=14)

Days after lysis or medical therapy

Van Belle et al. Circulation. 1998;97:26-33.

angioscopy follow up 6 months after ses or bms implantation

Edge

Body

Overlapping

Segment

Angioscopy Follow-up 6 Months After SES or BMS Implantation

Grade 0

No neointima

Grade 1

Thin neointima

Grade 2

Full neointima

Visible

Thrombus

P=.70

P<.001

>80%

P=.63

P=.80

P<.0005

P<.05

100

2.5

*

80

2

P=.031

*

60

Frequency of Persistence

of Thrombus (%)

1.5

*

Stent Coverage Grade

40

*P<.001 comparedwith the corresponding

segment in the BMS.

1

20

0.5

0

0

n=7

SES

n=7

BMS

n=28 n=33 n=5

BMS

n=21 n=33 n=12

SES

(N=46, 66 lesions: 33 SES, 33 BMS)

Takano M, et al. Eur Heart J. 2006;27:2189-2195.

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 1997-2002
  • Among first anterior STEMI patients echoed within 72 hours LV clot was seen in 23.5%. (36/153)

* STEMI pts managed with lytic or medical mgt

Porter A et al. Coron Artery Dis. 2005 Aug;16(5):275-9

slide6

Positive Feedback Loops

Thrombin

“Amplification”

“Burst”

“Cascade”

“Activation”

Confidential. Do Not Distribute. Prasugrel is not FDA indicated for use.

meta analysis of anticoagulation
Meta Analysis of Anticoagulation

Rates of Recurrent MI

Rothberg 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 MIRx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg

Efficacy

Safety

30

Major Bleed

Tranfusion

20

Minor Bleed

%

15

Death,MI,CVA

8

10

5

2

1

1

1

1

1

0

ASA

Coumadin

Combo

Rate of

Discontinuation

10%

19%

20%

van Es et al Lancet 360:109,2002

oasis 2 impact of anticoagulation discontinuation
OASIS 2: Impact of Anticoagulation Discontinuation

P=0.02

P=0.33

P=0.005

P=0.16

21.3

20

18.5

Std Rx

16.5

Oral A/C + ASA

15

% Pts

11.9

9

8.9

10

7.8

6.1

5

0

Compliance: Good Bad Good Bad(% on Oral AC) >70 % < 70% > 70% < 70%

CVD,MI,CVA

CVD, MI, CVA, Rehosp UA

OASIS Inv JACC 37:475,2001

esteem primary endpoint
ESTEEM: Primary Endpoint

Death/MI/Severe Recurrent Ischemia

20%

  • The primary endpoint was lower for pooled ximelagatran compared with placebo (12.7% vs 16.3%, HR 0.76, p=0.03)
  • Ximelagatran Dc’d in 7% of pts due to LFT abnormalities

% Death/MI/Recurrent Ischemia

16.3%

p=0.03

15%

12.7%

10%

5%

n=1,245

n=638

0%

Placebo

Pooled Ximelagatran

Oral direct thrombin inhibitor (IIa), no coagulation monitoring is required, fixed dose, eval in STEMI or non-STEMI

factor xa inhibition at the intersection of the intrinsic and extrinsic pathways
Factor Xa Inhibition: At The Intersection of the Intrinsic and Extrinsic Pathways

TF (Tissue Factor)

XIa

XI

Intrinsic Pathway

IX

IXa

VIIa + TF

VII

Extrinsic Pathway

VIIIa

X

Xa

If either the Intrinsic or Extrinsic pathway is activated, Factor Xa inhbitorsblock the final common coagulation pathway to form thrombin by blocking Factor XA

Va

IIa (Thrombin)

II

Fibrinogen

Fibrin

meeting the unmet needs in long term anticoagulation in acs
Meeting the Unmet Needs in Long Term Anticoagulation in ACS
  • Safe
  • Effective
  • Ease of use
    • No monitoring
    • Unaffected by diet
new antithrombins
New Antithrombins

ORAL

PARENTERAL

TF/VIIa

TFPI (tifacogin)

TTP889

IX

X

APC (drotrecoginalfa)

sTM (ART-123)

RivaroxabanApixabanLY517717YM150

DU-176bPRT-054021

IXa

VIIIa

Va

AT

Xa

FondaparinuxIdraparinux

II

DX-9065aOtamixaban

XimelagatranDabigatran

IIa

Fibrinogen

Fibrin

Adapted from Weitz & Bates, J ThrombHaemost2005

rivaroxaban inhibits thrombin generation
In vitro: platelet-rich human plasma activated by diluted tissue factor

120

Control

100

5 nM Rivaroxaban

10 nM Rivaroxaban

20 nM Rivaroxaban

80

50 nM Rivaroxaban

80 nM Rivaroxaban

Thrombin concentration (nM)

60

100 nM Rivaroxaban

40

20

0

0

10

20

30

40

50

Time (minutes)

Rivaroxaban Inhibits Thrombin Generation

Gerotziafas & Samama. ICT 2004, Ljubljana, Slovenia, ISTH 2005, Sydney, Australia

oral factor xa inhibitors in clinical development
Oral Factor Xa Inhibitors In Clinical Development

Rivaroxaban (Bayer) Phase IIb

Phase III

Apixaban (BMS) Phase III

YM150 (Astellas) Phase IIb

DU-176b (Daiichi) Phase IIb

LY517717 (Lilly) Phase IIb

813893 (GSK) Phase I/II

PRT054021(Portola) Phase II

factor xa inhibitors in development
Factor Xa Inhibitors in Development

*Prevention of VTE after major orthopaedic surgery, unless indicated