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 rupture 1 Plaque erosion 2

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

NormalFatty

streakFibrousplaque

Athero-scleroticplaque

Plaquerupture/fissure &

thrombosisMyocardial infarction

Ischemicstroke/TIA †

Critical leg ischemia

Clinically silent

Cardiovasculardeath

Increasing age

Stable anginaIntermittent claudication

Unstableangina }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

PATHOPHYSIOLOGY

UAP/NSTEMI

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 Med1986;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 CoronarySyndromes

� Anti-ischemic treatment

� Antiplatelet agents

� Anticoagulants

� Revascularization/Reperfusion/Thrombolysis

� Long term treatment/secondary prevention

Targets for antithrombotics

Tissue factor

Plasma clottingcascade

Prothrombin

Thrombin

Fibrinogen Fibrin

Thrombus

Platelet aggregation

Conformational activation of GPIIb/IIIa

Collagen

Thromboxane A2

ADP

AT

AT

Aspirin

ClopidogrelPrasugrelAZD 6140

GPIIb/IIIainhibitors

BivalirudinHirudin

Dabigatran

FactorXa

Fondaparinux

LMWHHeparin

Direct Xa inhib

IschemicComplicationsIschemic

ComplicationsHemorrhage

HITHemorrhage

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

Intrinsicpathway

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;267:12528-38Turpie et al. N Engl J Med 2001;344:619-25

In 20,078Patients

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

Fondaparinux2.5 mg s.c. od up to 8 days

Aspirin, Clopidogrel, anti-GPIIb/IIIa, planned Cath/PCI as per local practice

Randomization

Enoxaparin1 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-.e102. 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

ObjectivesPrimary 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

ObjectivesPrimary 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-.e102. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Fondaparinux: 2.2% (217 events)Enoxaparin: 4.1% (412 events)

Days

Cumulative Hazard

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

Cumulative Hazard

0.0

0.01

0.02

0.03

0 3 6 9 12 15 18 21 24 27 30

HR: 0.83 95% CI: 0.71-0.97p=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

Cumulative Hazard

HR: 0.8995% CI: 0.82-0.97 p=0.007

Enoxaparin

Fondaparinux

0.02

0.04

0.06

0.08

0.10

0.12

0.14

12,092 Pasien

Fondaparinux 2.5 mg s.c. once dailywill show superior efficacycompared 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 1UFH not indicated

Stratum 2UFH Indicated

Fondaparinux s.c. 2.5 mg od/8 days*

Placebo8 days*

UFH i.v. 24-48 h

Fondaparinux s.c. 2.5 mg od/8 days*



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



ARI/PRN/06/27/09/13

The Benefit of FondaparinuxAppeared 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)

Fondaparinuxn=6056

Placebo/UFHn=6036

7.4% 8.9%

6.1% 7.0%

1.6% 2.3%

p value9-day outcomes



ARI/PRN/06/27/09/13

UFH or placebo

Fondaparinux

HR: 0.86

95% CI: 0.77-0.96

p=0.0080

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

Cum

ula

tive H

aza

rd

Days

Fondaparinux Significantly Reduced the Rate of Death/Reinfarction up to Day 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

Cum

ula

tive H

aza

rd

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

Fondaparinux: 1.0% (61 events)UFH or placebo: 1.3% (79 events)



ARI/PRN/06/27/09/13

The OASIS-6 Trial Group. JAMA 2006;295:1519-30ACC 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



A Significant Benefit of Fondaparinuxin the 5436 Patients Who Received Thrombolytics

(sub group analysis OASIS 6)

A Significant Benefit of Fondaparinuxin the 2867 Patients Who Received

No Reperfusion Therapy (Sub Group Analysis OASIS 6)

The OASIS-6 Trial Group. JAMA 2006;295:1519-30ACC 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



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.

� Fondaparinuxmay therefore become the new reference anticoagulant drug in UA/NSTEMI and STEMI patients

Patophysiology of ACS: Role of Thrombosis

Health & Medicine

Transcript of Patophysiology of ACS: Role of Thrombosis