Patophysiology of ACS: Role of Thrombosis

PATHOPHYSIOLOGY of ACS :
Role of Thrombosis
Antonia Anna Lukito

What is Atherothrombosis?
Atherothrombosis is characterized by a sudden
(unpredictable) atherosclerotic plaque disruption
(rupture or erosion) leading to platelet activation and
thrombus formation
Atherothrombosis is the underlying condition that
results in events leading to myocardial infarction,
ischemic stroke, and vascular death
Plaque rupture1 Plaque erosion2
1. Falk E et al. Circulation 1995; 92: 657–71. 2. Arbustini E et al. Heart 1999; 82: 269–72.

Plaque Rupture With Thrombosis Process

Normal
Fatty
streak
Fibrous
plaque
Athero-
sclerotic
plaque
Plaque
rupture/
fissure &
thrombosis
Myocardial
infarction
Ischemic
stroke/TIA†
Critical leg
ischemia
Clinically silent
Cardiovascular
death
Increasing age
Stable angina
Intermittent claudication
Unstable
angina
}ACS*
The Development of Atherothrombosis –
a Generalized and Progressive Process
Adapted from: Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6, and
Aronow WS, Ahn C. Am J Cardiol 194; 74: 64–5.
*ACS, acute coronary syndrome
†TIA, transient ischemic attack

Causes of UA/NSTEMI*
• Thrombus or thromboembolism, usually arising on disrupted or
eroded plaque
– Occlusive thrombus, usually with collateral vessels†
– Subtotally occlusive thrombus on pre-existing plaque
– Distal microvascular thromboembolism from plaque-associated
thrombus
– Thromboembolism from plaque erosion
• Non–plaque-associated coronary thromboembolism
• Dynamic obstruction (coronary spasm‡ or vascoconstriction) of
epicardial and/or microvascular vessels
• Progressive mechanical obstruction to coronary flow
• Coronary arterial inflammation
• Secondary UA
• Coronary artery dissection§
*These causes are not mutually exclusive; some patients have 2 or more causes. †DeWood MA, et al. N Engl J Med
1986;315:417–23. ‡May occur on top of an atherosclerotic plaque, producing missed-etiology angina or UA/NSTEMI.
§Rare. Modified with permission from Braunwald E. Circulation 1998;98:2219–22. Anderson JL, et al. J Am Coll Cardiol.
2007;50:e1-e157, Table 3.

Acute Coronary Syndrome (ACS)
A Major Cause of Mortality and Morbidity
UA/NSTEMI
• In-hospital death and re-infarction: 5-10%1
• Six-month mortality in the GRACE registry2 (from admission to 6 months):
- NSTEMI: 13%
- UA: 8%
1.Grech & Ramsdale. BMJ 2003;326:1259-61;
2Fox. Am Heart J 2004:148:S40-5;
3.Antman et al. Circulation 2004;110:e82-292;
4.van de Werf et al. Eur Heart J 2003;24:28-66
STEMI
• 1/3 of STEMI patients will die within 24 h of the onset of ischemia1
• In-hospital death and reinfarction: 8-10%3
• One-month mortality: 6-7%4
ARI/PRN/06/27/09/13

Therapeutic Options in Acute Coronary
Syndromes
Anti-ischemic treatment
Antiplatelet agents
Anticoagulants
Revascularization/Reperfusion/Thrombolysis
Long term treatment/secondary prevention

Targets for antithrombotics
Tissue factor
Plasma clotting
cascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational
activation of GPIIb/IIIa
Collagen
Thromboxane A2
ADP
AT
AT
Aspirin
Clopidogrel
Prasugrel
AZD 6140
GPIIb/IIIa
inhibitors
Bivalirudin
Hirudin
Dabigatran
Factor
Xa
Fondaparinux
LMWH
Heparin
Direct Xa inhib

Ischemic
Complications
Ischemic
Complications
Hemorrhage
HIT
Hemorrhage
HIT
► Death
► MI
► Urgent TVR
► Death
► MI
► Urgent TVR
► Major Bleeding
► Minor Bleeding
► Thrombocytopenia
► Major Bleeding
► Minor Bleeding
► Thrombocytopenia
Composite Adverse Event EndpointsComposite Adverse Event Endpoints
Evolving Paradigm for Evaluating ACS
Management Strategies

Major Bleeding is Associated with an Increased
Risk of Hospital Death in ACS Patients
Moscucci et al. Eur Heart J 2003;24:1815-23
GRACE Registry in 24,045 ACS patients
*After adjustment for comorbidities, clinical presentation, and hospital therapies.
**p<0.001 for differences in unadjusted death rates
OR (95% CI)
1.64 (1.18 to 2.28)*
0
Overall ACS UA NSTEMI STEMI
10
20
30
40
**
**
**
**
5.1
18.6
3.0
16.1
5.3
15.3
7.0
22.8
Inhospitaldeath(%)
Inhospital major bleeding YesNo
ARI/PRN/06/27/09/13

UFH LMWH Pentasaccharides
Presence of cofactor required +++ +++ +++
Renal clearance of clinical
relevance
± ++ +
Non-specific protein binding +++ + +
Bioavailability by s.c or oral
administration
+
( for s.c administration )
++ +++
Predictability of pharmacological
effect
- ++ ++
Inhibition of thrombin generation ++ ++ ++
Inhibition of thrombin activity +++ + -
Inhibition of bound – thrombin - - -
Rebound of thrombin generation
after discontinuation
+++ ++ -
Platelet Activation +++ + -
Immune thrombocytopenia +++ + -
Decreased bone density +++ + -
A comparison of relevant pharmacological properties of the
different thrombin inhibitors in current clinical use
Properties are semiquantitatively graded as : - absent,± barely present, + present-to a low degree, ++ present-to an intermediate degree, +++ present-to a high degree
Raffaele D.C, Steen H, Lars W, Giancarlo A, Fedor B, Colin B , Jorgen J, Steen DK, Gilles M, Agneta S, Freek WAV, Jeffrey W. Anticoagulants in Heart Disease :
Current Status and Perspectives. Eur Heart J 2007 ; 28 : 885-9

Fondaparinux Sodium, 2.5 mg/0.5 ml solution for injection,
in pre-filled syringe
is a pure factor Xa inhibitor that is given in a once daily
injections
unlike heparins or LMWH, fondaparinux is a synthetic
compound and not derived from animal products
has rapid onset of action, 100% bioavailability and undergoes
no metabolism or protein binding
(other than its target)
has been extensively studied for prevention of VTE where it was
superior to enoxaparin
The 1st Synthetic Pentasaccharide of FXa Inhibitor

Thrombin
Fibrinogen
Extrinsic
pathway
Intrinsic
pathway
AT
Fondaparinux
XaAT
Antithrombin
Fibrin clot
Xa
Pro-thrombin
Due to its synthetic nature, high efficacy, acceptable safety profile, and
once-daily use without any laboratory monitoring,
fondaparinux represents a major therapeutic advance in the prevention and
treatment of thrombotic diseases
Reutilized
Olson et al. J Biol Chem 1992;267:12528-38
Turpie et al. N Engl J Med 2001;344:619-25

In 20,078
Patients
In 12,092
Patients

OASIS 5: An International, Multicenter, Randomized, Double-
Blind, Double-Dummy Trial in 41 Countries
20,078 patients with UA/NSTEMI20,078 patients with UA/NSTEMI
Fondaparinux
2.5 mg s.c. od up to 8 days
Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned
Cath/PCI as per local practice
Randomization
Enoxaparin
1 mg/kg s.c. bid for 2-8 days
1 mg/kg s.c. od if ClCr<30mL/min
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 1464-76
Vital status ascertained in 20,066 (99.9%)
Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5

Study Objectives and Outcomes
Outcomes (centrally adjudicated)
Primary efficacy: 1st occurrence of the composite of death, MI, or refractory
ischemia (RI) up to day 9
Primary safety: Major bleeding up to day 9
Risk benefit: Death, MI, refractory ischemia, major bleeds up to day 9
Secondary: Above & each component separately at days 30 and 180
Objectives
Primary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective: To determine whether fondaparinux was
superior to enoxaparin in preventing major
bleeding
Objectives
Primary efficacy objective: To demonstrate non-inferiority of fondaparinux
compared with enoxaparin
Primary safety objective: To determine whether fondaparinux was
superior to enoxaparin in preventing major
bleeding
1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10
2. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Fondaparinux: 2.2% (217 events)
Enoxaparin: 4.1% (412 events)
Days
CumulativeHazard
0.0
0.01
0.02
0.03
0.04
0 1 2 3 4 5 6 7 8 9
HR: 0.52
95% CI: 0.44-0.61 p<0.001
Enoxaparin
Fondaparinux
Fondaparinux Patients Experienced Half the Rate of Major
Bleeding Than Enoxaparin Patients at Day 9 (Primary Safety)

Fondaparinux Significantly Reduced Mortality vs.
Enoxaparin up to Day 30
Days
CumulativeHazard
0.0
0.01
0.02
0.03
0 3 6 9 12 15 18 21 24 27 30
HR: 0.83
95% CI: 0.71-0.97
p=0.02
Enoxaparin
Fondaparinux
0.04

Fondaparinux Reduced the Rate of the Composite of
Death, MI or Stroke up to 6 Months
0.0
Days
0 20 40 60 80 100 120 140 160 180
CumulativeHazard
HR: 0.89
95% CI: 0.82-0.97
p=0.007
Enoxaparin
Fondaparinux
0.02
0.04
0.06
0.08
0.10
0.12
0.14

Fondaparinux 2.5 mg s.c. once daily
will show superior efficacy
compared with usual care
Study Hypothesis OASIS 6

Fondaparinux
An International, Multicenter, Randomized, Double-Blind, Double-
Dummy Trial in 41 Countries
12,092 patients with STEMI
<12 h of symptom onset
Randomization
Standard Care
Reff :
1. ArixtraTM PI BPOM 4 October 2010, GDS04/IPI04 (23 January 2007).
2. The OASIS 6 trial. Effect of Fondaparinux on Mortality and Reinfarction in Patients with Acute ST-segment elevation MI.
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

• Vital status known at hospital discharge in 12,085 (99.9%)
• Follow-up: Day 30=12,072 (99.8%) – Study end=12,052 (99.7%)
12,092 patients with STEMI12,092 patients with STEMI
Thrombolytics (SK, TPA, TNK, RPA),
Primary PCI or no reperfusion
Randomization
Stratum 1
UFH not indicated
Stratum 2
UFH Indicated
Fondaparinux s.c.
2.5 mg od/8 days*
Placebo
8 days*
UFH i.v.
24-48 h
Fondaparinux s.c.
2.5 mg od/8 days*
Reff :
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

Study Objectives
Primary efficacy objective
To evaluate whether fondaparinux was superior to usual care (UFH or
placebo) in preventing death or recurrent MI in patients with STEMI
Primary safety objective
To evaluate the safety of fondaparinux compared with usual care, in
terms of severe bleeding, in patients with STEMI
Primary efficacy objective
To evaluate whether fondaparinux was superior to usual care (UFH or
placebo) in preventing death or recurrent MI in patients with STEMI
Primary safety objective
To evaluate the safety of fondaparinux compared with usual care, in
terms of severe bleeding, in patients with STEMI
Reff :
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

The Benefit of Fondaparinux
Appeared at Day 9
HR 95%CI
Death/Reinfarction
Death
Reinfarction
0.83 0.73-0.94 0.003
0.87 0.75-1.00 0.043
0.67 0.52-0.88 0.004
1.0 100.1
Fondaparinux better Placebo/UFH better
Hazard Ratio (log scale)
Fondaparinux
n=6056
Placebo/UFH
n=6036
7.4% 8.9%
6.1% 7.0%
1.6% 2.3%
p value9-day outcomes
Reff :
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

UFH or placebo
Fondaparinux
HR: 0.86
95% CI: 0.77-0.96
p=0.008
0
0.02
0.04
0.06
0.08
0.10
0.12
0.14
0.16
0 3 6 9 12 15 18 21 24 27 30
CumulativeHazard
Days
Fondaparinux Significantly Reduced the Rate
of Death/Reinfarction up to Day 30
Reff :
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

0
0.002
0.004
0.006
0.008
0.010
0.012
0.014
0.016
HR: 0.79
(95% CI: 0.58-1.09)
p=0.15
CumulativeHazard
Days
0 3 6 9 12 3015 18 21 24 27
UFH or placebo
Fondaparinux
There Was No Increased Risk of 30-Day Severe Bleeding in
the Fondaparinux Group
UFH or placebo: 1.3% (79 events)
Reff :
Jama 2006; 259:1519-30.
ARI/PRN/06/27/09/13

The OASIS-6 Trial Group. JAMA 2006;295:1519-30
ACC Presentation. Atlanta, March 2006
HR 95%CI
Death/reinfarction, day 30
Death, day 90/180
Severe bleeding, day 9
0.79 0.68-0.92
0.85 0.73-0.99
0.66 0.44-0.98
1.0 100.1
Hazard Ratio
(log scale)
A Significant Benefit of Fondaparinux
in the 5436 Patients Who Received Thrombolytics
(sub group analysis OASIS 6)

A Significant Benefit of Fondaparinux
in the 2867 Patients Who Received
No Reperfusion Therapy (Sub Group Analysis OASIS 6)
The OASIS-6 Trial Group. JAMA 2006;295:1519-30
ACC Presentation. Atlanta, March 2006
HR 95%CI
Death/reinfarction, day
30
Death, day 90/180
Severe bleeding, day 9
0.80 0.65-0.98
0.84 0.69-1.01
0.84 0.47-1.50
1.0 100.1
Hazard Ratio
(log scale)

Take Home Messages
OASIS 5 & 6 has identified an excellent regime for
anticoagulation in ACS.
While other antithrombotic agents reduced death/MI but
increased bleeding, Fondaparinux reduced death/MI without
increasing bleeding events.
The OASIS 5 & 6 trials showed that Fondaparinux 2.5 mg once
daily was effective & safe in the full spectrum of ACS with up to
50% significantly fewer bleed vs. LMWH.
Fondaparinux may therefore become the new reference
anticoagulant drug in UA/NSTEMI and STEMI patients

Patophysiology of ACS: Role of Thrombosis

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