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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
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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 ?
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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%
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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”
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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
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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 ?
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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
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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
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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 ?
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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.
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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
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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
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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
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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 ?
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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
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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 ?
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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