13/03/2012

1

Acute Coronary Syndrome (ACS)

Understanding the need for fast and potent  antithrombotic agents through thrombus analysis

Johanne Silvain, MD-PhD

Pitié-Salpêtrière Hospital Paris - France

1 Université Paris 62I NSERM UMRS937 – Equipe 3 – Pr G. MONTALESCOT / Pr JP. COLLET3 Département de Cardiologie Médicale du Groupe Hospitalier Pitié‐Salpêtrière

http://www.action-coeur.org/

DISCLOSURE STATEMENT OF FINANCIAL INTERESTJohanne SILVAIN MD, PhD

Research Grants to institution from Sanofi-Aventis, Boehringer-Ingelheim, Daiichi-Sankyo, Eli Lilly, Brahms, INSERM, Fédération Française de Cardiologie and Société Française de Cardiologie

Consulting Fees from Daiichi-Sankyo, Eli Lilly

Lecture Fees from AstraZeneca, Cordis, Daiichi Sankyo, Eli Lilly, Stentys and Servier

Disclosures

13/03/2012

2

ACS Guidelines 2010/20111- Aspirin LD 150-300mg (MD 75-100mg)

2- P2Y12 Inhibitor ASAP

Low life-threatening bleeding risk = Prasugrel 60/10mg TRITON

TRITON STEMI

NSTE-ACS

STEMI

Wiviott SD. N Engl J Med 2007

Montalescot G. Lancet 2009

= Prasugrel 60/10mg

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

13/03/2012

3

Thrombus in STEMI

Svilaas, T. et al. NEJM 2008

TIMI 0-1

TIMI 2

TIMI 3

Visible prePCI thrombus in 46.3% of patients

TAPAS Trial n= 1071 STEMI patients Kramer Study n= 1315 STEMI patients

Kramer M. et al. Circulation 2008

Aspirated thrombus in 74.6% of patients

24.5%29.5%

13/03/2012

4

1,342 (80.5%) angiograms of STEMI patientsenrolled in ASSENT-4 PCI.

Thrombus in STEMI

Zalewsky K. et al. JACC 2011

Residual TIMI thrombus grade 2 and/or distal embolization and/or slow flow

post-PCI THROMBUS BURDEN

OR 2.43 for 90-day mortality(95% CI 1.3-4.51,p=0.0052)

p=0.002

%

05

101520

13.4%

19.7%

Thrombus in STEMI

Zalewsky K. et al. JACC 2011

AVOID

Fibrinolytic therapy

PCI + StentLD of thienopyridine

USE

Gp IIb/IIIa inhibitorsNEUTRAL

“longer time interval from SO to PCI (ischemic time) is independently associated with a larger residual thrombus”

13/03/2012

5

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

Incidence of distal embolization

6.3% of angiographicvisible distal embolization(Thrombus fragment)

Lower MBG and ST-segment resolutionHigher enzyme levelHigher risk of re-MIHigher mortality (ns)

Distal embolization in STEMI

Fokkema M. et al. EHJ 2009

883 patients with STEMI undergoing pPCI

Platelet poor /Fibrin rich thrombus = More distal embolization

13/03/2012

6

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

3,627 patients with NSTE-ACS (moderate to high-risk) undergoing PCI

Thrombus in NSTE-ACS

530 (15%) patients

Goto K. et al. JACC Cardiovasc Intervention 2011

pre-PCI THROMBUS Impact on prognosis ? Predictors of Thrombus ?

13/03/2012

7

Adapted from Goto K. et al. JACC Cardiovasc Intervention 2011

Thrombus in NSTE-ACS

0

10

20

30

40

50

60

70

Blush <3prePCI

Blush <3postPCI

DVE / no-reflow

63.1%

37.2%

21.6%

13.5%

5.5%0.6%

0

2

4

6

8

10

12

14

MACE ST

13.0%

9.4%

2.8%

1.1%

Angiographic Endpoints Ischemic Endpoints

30 days follow up

p=0.0023

p=0.009

p=<0.0001 for all

Thrombus -Thrombus +

Goto K. et al. JACC Cardiovasc Intervention 2011

Thrombus in NSTE-ACS

05

101520253035404550

30.8%32.1%

37.2%

Protectors of thrombus formation

Thienopyridines on admission OR 0.77 [95% CI: 0.59 to 0.99], p=0.04

Planned GPI use OR 0.80 [95% CI: 0.65 to 0.98], p=0.03

1- optimal anticoagulation2- optimal antiplatelet therapy

Patients with thrombus

13/03/2012

8

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

Key elements of thrombus formation 

Bruce and Barbara Furie . N Engl J Med 2008;359:938‐49

Platelets

Tissue Factor

FibrinFibrin + Tissue Factor

Platelets + Tissue Factor

Platelets +Fibrin +Tissue Factor

13/03/2012

9

Therapeutic targets ?

Mouse Models of In Vivo Thrombosis. 

1- Tissue Factor

2- Platelets

3- Thrombin

4- Fibrin mesh

Thrombus in STEMI patients. 

Weisel JW et al . Science 2009

Anticoagulants

Fibrinolytics < PCI

Antiplatelet agents

?

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

13/03/2012

10

Beygui et al. Circulation 2006;113;e21‐e23

Generation of the Hypothesis … “Time make the difference”   

BLATE OCCLUSION

AEARLY OCCLUSION

60 min 

6 Hours

?

How time affects the dynamic process of thrombus formation inpatients  presenting an ST‐elevation Myocardial Infarction (STEMI) ?

Question ? 

Unique opportunity to study thrombuscomposition, dynamic formation andarchitecture in vivo

In HumanIn a mouse

Mouse Models of In Vivo Thrombosis. 

13/03/2012

11

Microscope Analysis

Random assignation of 10+ areas to control for heterogenity  

n= 10+ frames per thrombus; n = 408 “boxes” in each grid

Image Analysis

Silvain et al. J Am Coll Cardiol 2011

13/03/2012

12

Fibrin fib

ers

Platele

ts

Red C

ells

Cholester

ol crys

tal

White C

ells

Mixed C

ells-F

ibrin0

20

40

60

80

100 %

Thrombus Composition Thrombus Composition Results (1)

40%60%

Identification of  crystal like structure* – potentially cholesterol plaque debris

Platelet rich Thrombus <3 hoursPlatelet rich Thrombus <3 hours

13/03/2012

13

Thrombus with identification of a) White Cell b) platelets c) Fibrin fibers d) Red Cell

Mixed Thrombus 3‐6 hoursMixed Thrombus 3‐6 hours

Fibrin rich Thrombus >6 hoursFibrin rich Thrombus >6 hours

13/03/2012

14

0 200 400 600 8000

20

40

60

80

100 FibrinRed CellsPlateletsWhite CellsMixed Cells‐FibrinCholesterol Crystals

Ischemic Time (min)

Thrombu

s Co

mpo

sitio

n (%

)Dynamic thrombus formationDynamic thrombus formation

Results (2) Influence of TimeInfluence of Time

Fibrin r=0.38, p=0.01

Platelets r=‐0.34, p=0.02

‐ X2 rate of fibrin rich thrombus   adjOR 2 [1.03‐3.7], p=0.001 ‐ 50% reduction in platelet content  adjOR 0.5  [0.27‐0.94], p=0.001 

Every additionnal hour of Ischemic time 

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

13/03/2012

15

A crucial timing for anti‐thrombotic treatment

Platelet and thrombin inhibition with fast acting and potent drugs ++ Silvain et al. J Am Coll Cardiol 2011

Silvain et al . Circulation CVI 2011

4 hours after administration

PharmacodynamicsNew P2Y12 Inhibitor

Silvain et al. Circulation CVI 2010

Guidelines 2010 – ACS

TRITON STEMI

PLATO STEMI

New P2Y12 inhibitors

13/03/2012

16

Ischemic Time and risk of the patients

Risk Profile 

Ischemic Time (min)(Symptom Onset ‐ TTT)

60            120            180            240            300           360

High

Intermediate

Low

High Risk and long delay

FINESSE

Low Risk and short delay 

MISTRAL

High Risk and short delay

EUROTRANSFER

RELAX‐AMIOn Time‐2

FINESSE substudy

Studies with benefit of IIbIIIa inhibitors

Studies without benefit of IIbIIIa inhibitors

BRAVE‐3

Low Risk and long delay 

Interpretation of IIbIIIa clinical trials  

1‐ Is coronary thrombus frequent in STEMI ?

2‐ Is distal embolization important ? 

3‐What about thrombus in NSTE‐ACS ? 

4‐What do we know about thrombus formation and which are the therapeutic targets ?

5‐ Does time play a role ?   

6‐ How to interpret clinical trials  ?

7‐Which drug should you choose ? 

13/03/2012

17

Fibrin

Thrombin

Platelets

ANTICOAGULANTSFull dose Enoxaparin IVBivalirudin IVFondaparinuxHNF

PLATELET INHIBITORSAspirin AbciximabClopidogrel TirofibanPrasugrel EptifibatideTicagrelor CangrelorVoraxapar Elinogrel

FIBRINOLYTICS« Golden Hour »

FAST AND POTENT DRUGS +++

Conclusion 

Formation of a coronary thrombus is a fast evolving process with 3 major therapeutical target (thrombin, platelet and fibrin). 

Thrombus burden impacts myocardial reperfusion, patients prognosis and increases mortality

Thrombus studies highlight the crucial role of pharmacodynamic= fast‐acting antiplatelet  agent using a triple antiplatelet therapy (aspirin + new P2Y12 inhibitor + GIIbIIa inhibitors) and potent thrombin inhibitor especially in early STEMI presenters

Thrombus is present in STEMI and NSTE‐ACS and needs to be treated by PCI with an optimal timing and an  optimal antithrombotic therapy