LongTerm Management of Patients at Risk of Atherothrombosis

1
Long-Term Management of Patients at Risk of
Atherothrombosis
2
Pathogenesis of Atherothrombosis Long-Term
Outcome in Patients at Risk
3
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 65771. 2.
Arbustini E et al. Heart 1999 82 26972.
4
The Development of Atherothrombosis a
Generalized and Progressive Process
Adapted from Drouet L. Cerebrovasc Dis 2002
13(suppl 1) 16.
5
Atherothrombosis and Microcirculation
Adapted from Topol EJ, Yadav JS. Circulation
2000 101 57080, and Falk E et al. Circulation
1995 92 65771.
6
Major Clinical Manifestations of Atherothrombosis
Ischemic stroke
Transient ischemic attack
Myocardial infarction

• Angina
• Stable
• Unstable

• Peripheral arterial
• disease
• Intermittent claudication
• Rest Pain
• Gangrene
• Necrosis

Adapted from Drouet L. Cerebrovasc Dis 2002
13(suppl 1) 16.
7
Atherothrombosis is aLeading Cause of Death
Worldwide1
Mortality ()
Cardiovascular disease, ischemic heart disease
and cerebrovascular disease Worldwide defined as
Member States by WHO Region (African, Americas,
Eastern Mediterranean, European, South-East Asia
and Western Pacific)
1. The World Health Report 2001. Geneva WHO
2001.
8
Identifying Those at Risk of Atherothrombosis1,2

• Local factors
• Elevated prothrombotic factors fibrinogen, CRP,
  PAI-1
• Blood flow patterns, vessel diameter, arterial
  wall structure

• Systemic
• conditions
• History of vascular events
• Hypertension
• Hyperlipidemia
• Hypercoagulable states
• Homocystinemia

Atherothrombosis manifestations (myocardial
infarction, stroke, vascular death)

• Generalised
• disorders
• Obesity
• Diabetes

• Lifestyle
• Smoking
• Diet
• Lack of exercise

• Genetic
• Genetic traits
• Gender
• Age

1. Yusuf S et al. Circulation 2001 104 274653.
2. Drouet L. Cerebrovasc Dis 2002 13(suppl 1)
16.
9
Atherothrombosis is a Systemic Disease
Increased Risk of Stroke in Patients After a
Myocardial Infarction1
1. Lichtman JH et al. Circulation 2002 105
10827.
10
Atherothrombosis is a Systemic Disease
Long-Term Risk Increase for Stroke As a Function
of Coronary Calcification1
x 3.3
3.5
3.0
2.5

2.0
Risk increase
1.5
1.0
1.0
0.5
0.0
0100
101500
gt 500
Coronary calcium score
1. Vliegenthart R. Stroke 2002 33 4625.
11
Atherothrombosis is a Systemic Disease
Long-term Risk Increase for Myocardial
Infarction as a Function of Carotid Intima Media
Thickness1
4.0
x 3.61
3.5
3.0


2.5
Risk increase
2.0

1.5
1.0
1.0
0.5
0.0
1
2
3
4
5
Quintiles of carotid artery media thickness
1. OLeary DH. N Engl J Med 1999 340 1422.
12
Atherothrombosis is a Systemic Disease Increase
for Myocardial Infarction and Stroke as a
Function of ABI Measurement1
2.5
x 2.2
2.0

Risk increase

1.5

1.0
1.0
0.8
0.6
0.4
0.2
Ankle-brachial index (ABI) index
1. Dormandy JA, Creager MA. Cerebrovasc Dis 1999
9(suppl 1) 14.
13
Risk Assessment of Further Atherothrombotic
Events in Actual Practice1
Atherothrombotic Events/100 Patients Per Year
1. Caro J. Eur Heart J 2001 22(abstr suppl) 522.
14
Manifestations of Atherothrombosis are Commonly
Found in More than One Arterial Bed in an
Individual Patient1
Data from CAPRIE study (n19,185)
1. Coccheri S. Eur Heart J 1998 19(suppl) P1268.
15
Summary

• Atherothrombosis is characterized by a sudden
  plaque disruption leading to platelet activation
  and thrombus formation1
• Atherothrombosis is the common pathological link
  between all major clinical manifestations of
  vascular disease myocardial infarction, ischemic
  stroke and peripheral arterial disease2
• Patients with clinical manifestations of
  atherothrombosis in one vascular bed are not only
  at risk of a recurrent event in the same arterial
  distribution, but also at risk of developing
  ischemic events in other vascular beds3
• Atherothrombosis is one of the leading causes of
  death worldwide4

1. Drouet L. Cerebrovasc Dis 2002 13(suppl 1)
16. 2. Nenci GG. Eur Heart J 1999 1(suppl A)
A27A30. 3. Lichtman JH et al. Circulation 2002
105 10827. 4. The World Health Report
2001.Geneva WHO 2001.
16
The Burden of Atherothrombosis
17
Epidemiology of Atherothrombotic Manifestations
in the US

First attack only PAD patients in North America
(USA and Canada) symptomatic (37.5) and
asymptomatic (62.5)
1. American Heart Association. 2002 Heart and
Stroke Facts Statistical Update. 2. Ouriel K
et al. Lancet 2001 358 125764. 3. Weitz JI et
al. Circulation 1996 94 302649.
18
Epidemiology of Atherothrombotic Manifestations
in Europe1

According to patient age, sex and country of
originSpain, Italy, FranceUK, Germany,
Netherlands
1. Guillot F, Moulard O. Circulation 1998
98(abstr suppl 1) 1421.
19
Increasing Worldwide Prevalence of
Atherothrombotic Manifestations1
Prevalence 2000 2005
205.0 million (?5.1 since 1997)
222.2 million (?13.9 since 1997)
Populations aged gt 50 year old
9.1 million (?12.8 since 1997)
10.7 million (?32.7 since 1997)
Myocardial infarction
7.1 million (?11.8 since 1997)
8.4 million (?31.6 since 1997)
Ischemic stroke

Projected populations of people aged over 50
years, and estimated prevalence of myocardial
infarction and ischemic stroke cumulated in 14
countries Belgium, Canada, Denmark, Finland,
France, Germany,Italy, Netherlands, Norway,
Spain, Sweden, Switzerland, UK, USA
1. Guillot F, Moulard O. Circulation 1998
98(abstr suppl 1) 1421.
20
Hospitalizations in the US due to ACS1
1. Cairns J et al. Can J Cardiol 1996 12
127992.
21
European Survey of Acute Coronary Syndromesthe
ENACT Study1
Patient records from 3,092 ACS patients in the
EU (1999)

• Ratio of unstable angina (UA) to MI was 1.21.0
  overall and was similar in all European countries
• In patients with diagnosis of UA on admission, 9
  evolved to definite MI despite current treatment

17 Western European countries
1. Fox KA et al. Eur Heart J 2000 21 14409.
22
Epidemiology and Long-term Outcome of
Cerebrovascular Disease1

• Incident cases/year (per 1 million inhabitants)
• 500 transient ischemic attacks
• 2,400 strokes (75 first ever strokes)
• in 3 months 480 (20) deaths
• in 1 year 700 (29) deaths 600 (25) dependent
  survivors 1,100 (46) independent survivors
• Prevalent cases (per 1 million inhabitants)
• 12,000 patients, of whom 800 (7) have recurrent
  stroke every year

1. Hankey GJ, Warlow C. Lancet 1999 354 145763.
23
Causes of Death During Different Time Intervals
after First-Ever Stroke1
1. Hankey GJ. Stroke 2000 31 20806.
24
5-Year Mortality Risk in Cerebrovascular Patients1
1. Sacco RL et al. Neurology 1994 44 62634.
25
Long-term Outcome of Peripheral Arterial Disease
(PAD)1

• Causes of death
• 55 coronary artery disease
• 10 cerebrovascular disease
• 25 non-vascular
• lt 10 other vascular

100
80
Survival
60
Patients ()
Myocardial
infarction
40
Intervention
20
Amputation
0
0
1
2
3
4
5
6
7
8
9
10
Time (years)

• 1. Ouriel K. Lancet 2001 358 125764.

26
Peripheral Arterial Disease (PAD) and All-Cause
Mortality1
1.00
Normal Subjects
0.75
Asymptomatic LV-PAD
0.50
Survival
Symptomatic LV-PAD
0.25
Severe Symptomatic LV-PAD
0.00
0
2
4
6
8
10
12
Year
Kaplan-Meier survival curves based on mortality
from all-causes Large-vessel PAD
1. Criqui MH. Vasc Med 2001 6(suppl 1) 37.
27
Mortality in Patients with Severe Peripheral
Arterial Disease (PAD)
Relative 5-Year Mortality
1. Criqui MH. Vasc Med 2001 6(suppl 1) 37. 2.
McKenna M et al. Atherosclerosis 1991 87
11928. 3. Ries LAG et al. (eds). SEER Cancer
Statistics Review, 19731997. US National Cancer
Institute 2000.
28
Risk of a Second Vascular Event
Sudden death defined as death documented within
1 hour and attributed to coronary heart disease
(CHD) Includes only fatal MI and other CHD
death does not include non-fatal MI
1. Adult Treatment Panel II. Circulation 1994
89133363. 2. Kannel WB. J Cardiovasc Risk 1994
1 3339. 3. Wilterdink JI, Easton JD. Arch
Neurol1992 49 85763. 4. Criqui MH et al. N
Engl J Med 1992 326 3816.
29
Economic Impact of Coronary Heart Disease (CHD)
and Stroke1
Direct versus Indirect Costs (US)
70
60

• Direct costs
• Hospital/nursing home
• Physicians/other professionals
• Drugs
• Home health care

50
40
Costs (billion US)
30

• Indirect costs
• Loss of productivity due to morbidity or
  mortality

20
10
0
CHD
Stroke
1. American Heart Association. 2002 Heart and
Stroke Facts, Statistical Update.
30
Stroke Mean Cost as a Function of Long-Term Care
Destination1
Chronic long-termin-hospital care
56,114
33,208
Nursing home
33,062
Rehabilitation
Destination
22,297
Convalescent home
11,722
New housing
11,375
Return home
0
10,000
20,000
30,000
40,000
50,000
60,000
Euros
Excluding new acute hospitalization
1. Spieler J-F et al. Cerebrovasc Dis 2002 13
13241.
31
Acute Coronary Syndrome Average Cost in
Different European Countries (at 6 Months)1
France
Spain
Italy
UK
Germany
Netherlands
Initial hospital stay accounts for gt 80 of the
costs
1. Brown RE et al. Eur Heart J 2002 23 508.
32
Myocardial Infarction, Ischemic Stroke, and
Event-Free PAD Cost over 2 Years1

35,000
30,000
Estimated cost for
angioplasty or surgery
25,000
Follow-up and rehabilitation
20,000
treatment phase
Cost over 2 years from time of
presentation (US)
15,000
Acute
10,000
5,000
0
MI
Stroke
Event-free PAD
Including concomitant medication. Cost
estimates based on Medicare reimbursement rates
(US, 1997) and reference 1.
1. Hunink MG et al. J Vasc Surg 1994 19 63241.

33
Burden of AtherothrombosisSummary

• Atherothrombosis is a prevalent and deadly
  disease
• Manifestations of atherothrombosis (including
  acute cardiovascular disease, ischemic heart
  disease and stroke) constitute the leading cause
  of death in developed countries, causing over
  half of all deaths annually in North America and
  Europe1
• Myocardial infarction (MI) and stroke alone are
  responsible for a significant health burden1
• Peripheral arterial disease (PAD) greatly
  increases the risk to patients of coronary artery
  and cerebrovascular disease2
• The economic burden of MI, stroke and PAD is
  considerable.3

1. The World Health Report 2001. Geneva WHO
2001. 2. Criqui MH. Vasc Med 2001 6(suppl 1)
37. 3. American Heart Association. 2002 Heart
and Stroke Facts, Statistical Update.
34
The Role of Platelets in Atherothrombotic Disease
35
Hemostatic Plug Formation
Adapted from Ferguson JJ. The Physiology of
Normal Platelet Function. In Ferguson JJ,
Chronos N, Harrington RA (Eds). Antiplatelet
Therapy in Clinical Practice. London
MartinDunitz 2000 pp.1535.
36
Platelet Adhesion and Activation
Aggregation of platelets into a thrombus
Platelets adhering to damaged endothelium and
undergoing activation
Normal platelets in flowing blood
Platelet thrombus
Platelets adhering to subendothelial space
Platelets
Endothelial cells
Subendothelial space
Adapted from Ferguson JJ. The Physiology of
Normal Platelet Function. In Ferguson JJ,
Chronos N, Harrington RA (Eds). Antiplatelet
Therapy in Clinical Practice. London
MartinDunitz 2000 pp.1535.
37
Platelet Aggregation
Adapted from Kuwahara M et al. Arterioscler
Thromb Vasc Biol 2002 22 32934.
38
Key Mediators in Platelet Adhesion, Activation
and Aggregation
INJURY
vWF ADP-receptor
THROMBUS
Shear Forces
Adhesion
Activation
Aggregation

• vWF
• Thrombin
• Collagen
• Fibronectin

• Membrane changes
• Granule secretion
• GPIIb/IIIa expression
• Multiple agonists
• Feedback loops

• GPIIb/IIIa-mediated
• Fibrinogen
• vWF

1. Ferguson JJ. The Physiology of Normal Platelet
Function. In Ferguson JJ, Chronos N, Harrington
RA (Eds). Antiplatelet Therapy in Clinical
Practice. London Martin Dunitz 2000 pp.1535.
39
Plaque Disruption Leading to Atherothrombosis
Formation
Adapted from Falk E et al. Circulation 1995 92
65771.
40
Inflammatory Modulators Produced by Platelets

• Platelet-derived growth
• factor (PDGF)1
• Induces proliferation of smooth muscle cells

• Platelet-factor 41
• Mediates shear-resistant arrest of monocytes to
  endothelium

• CD154
• (CD40 ligand)1,4
• Regulates macrophage and smooth muscle cell
  functions

• RANTES2
• Influences macrophage adhesion to endothelial cell

PLATELET

• Transforming growth
• factor-ß5
• Stimulate smooth muscle cell biosynthesis

• Nitric oxide3
• Effects on monocyte, leucocyte, endothelium, and
  smooth muscle cells

• Thrombospondin1
• Interacts with cell surface receptors

1. Libby P, Simon DI. Circulation 2001 103
171820. 2. von Hundelshausen P et al.
Circulation 2001 103 17727. 3. Wever RMF et
al. Circulation 1998 97 10812. 4. Hermann A et
al. Platelets 2001 12 7482. 5. Robbie L,
Libby P. Ann N Y Acad Sci 2001 947 16779.
41
Role of PlateletsSummary

• Rupture or erosion of an atherosclerotic plaque
  exposes the thrombogenic core of the lesion and
  lead to adhesion and aggregation of platelets and
  thrombus formation1
• A large rupture typically results in the
  formation of a large thrombus that completely
  occludes the vessel, resulting in an acute
  vascular event2
• A smaller rupture may result in a mural thrombus
  that partially or transiently occludes the
  artery, causing acute ischemia and, in the long
  term, contributing to progression of
  atherothrombosis2
• Platelets produce several inflammatory modulators
  and may play a significant role in
  atherosclerotic development3

1. Ferguson JJ. The Physiology of Normal Platelet
Function. In Ferguson JJ, Chronos N, Harrington
RA (Eds). Antiplatelet Therapy in Clinical
Practice. London Martin Dunitz 2000 pp.1535.
2. Falk E et al. Circulation 1995 92 65771. 3.
Libby P, Simon DI. Circulation 2001 103
171820.
42
Long-Term Antiplatelet Therapyfor the Reduction
of Atherothrombotic Events
43
Antiplatelet Agents

• Thromboxane A2 inhibitor
• Acetylsalicylic acid (ASA)
• Phosphodiesterase inhibitor
• Dipyridamole
• Glycoprotein (GP) IIb/IIIa blockers
• Parenteral abciximab, eptifibatide, tirofiban
• ADP-receptor antagonists
• Clopidogrel
• Ticlopidine

44
Mode of Action of Antiplatelet Agents1
COX (cyclo-oxygenase) ADP (adenosine
diphosphate) TXA2 (thromboxane A2)
1. Schafer AI. Am J Med 1996 101 199209.
45
Strong Evidence BaseAntithrombotic Trialists
Collaboration1

• Objective
• to determine the effects of antiplatelet therapy
  among patients at high risk of occlusive vascular
  events
• Data reviewed
• 287 studies involving
• 135,000 patients in comparisons of antiplatelet
  therapy vs control
• 77,000 patients in comparisons of different
  antiplatelet regimens
• Main outcome measure
• serious vascular event non-fatal myocardial
  infarction, non-fatal stroke, or vascular death

1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
46
Antithrombotic Trialists Collaboration
Efficacy of Antiplatelet Therapy on Vascular
Events1
Control better
Antiplatelet better
Vascular events myocardial infarction, stroke
or vascular death
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
47
Antithrombotic Trialists Collaboration
Reduction in Risk of Non-Fatal Myocardial
Infarction1
Coronary artery disease, peripheral arterial
disease, high risk of embolism and other high
risk conditions (including hemodialysis,
diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
48
Antithrombotic Trialists Collaboration
Reduction in Risk of Non-Fatal Stroke1
Coronary artery disease, peripheral arterial
disease, high risk of embolism and other high
risk conditions (including hemodialysis,
diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
49
Antithrombotic Trialists Collaboration
Reduction in Risk of Vascular Deaths1
Coronary artery disease, peripheral arterial
disease, high risk of embolism and other high
risk conditions (including hemodialysis,
diabetes mellitus, carotid disease)
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
50
Antithrombotic Trialists Collaboration Evidence
Supports Low Dose ASA (75150 mg)1
ASA dose odds reduction 5001500 mg
daily 160325 mg daily 75150 mg daily lt 75 mg
daily Any ASA dose 23 2 (p lt 0.0001)
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
51
Effects of Antiplatelet Therapy on Vascular
Events in High Risk Patients
odds reduction(MI, stroke, orvascular death)
No. of trials with data
No. of patients
Treatment
All trials 195 144,051 251 Any
ASA 64 59,395 231 Dipyridamole 15 5,430 161 Ticl
opidine 42 5,430 321 Clopidogrel 1 19,185 302
The odds reduction for clopidogrel is the
result of a statistical analysis that uses data
from the Antithrombotic Trialists Collaboration
and the CAPRIE trial to estimate the effect of
clopidogrel vs placebo
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186. 2. Fisher LD et al. Am Heart J
2001 141 2632.
52
Antithrombotic Trialists Collaboration Efficacy
of Different Oral Antiplatelet Agents Relative to
ASA1
Antiplatelet agent odds reduction p
value Dipyridamole -2 NS Ticlopidine
12 NS Clopidogrel 10 0.03 All agents
8 0.0001
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186.
53
Effects of Different Antiplatelet Agents
Combined with ASA vs ASA Alone
In combination with ASA vs ASA alone
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186. 2. The CURE Trial
Investigators. N Engl J Med 2001 342 494502.
3. Data on file, 2002 p73 internal CSR-EFC 3307.
54
Antithrombotic Trialists Collaboration
Conclusion (I)

• Antiplatelet therapy should be considered
  routinely for all patients at risk
• Antiplatelet therapy reduces serious vascular
  events in a wide range of high-risk patients
• acute myocardial infarction (MI) and acute stroke
• prior MI and prior stroke/transient ischemic
  attack
• coronary artery disease (e.g. unstable angina,
  heart failure)
• peripheral arterial disease (e.g. intermittent
  claudication)
• high risk of embolism (e.g. atrial fibrillation)
• Other high risk factors (e.g diabetes)1
• Antiplatelet therapy should be continued
  long-term2,3

1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186. 2. Braunwald E et al. J Am
Coll Cardiol 2000 36 9701062. 3. Bertrand ME
et al. Eur Heart J 2000 21 140632.
55
Antithrombotic Trialists Collaboration
Conclusion (II)

• Low dose ASA (75150 mg daily) is as effective as
  higher ASA doses for long-term use1
• ADP-receptor antagonists are the only
  antiplatelet agents to have been shown to be
  superior to ASA in odds reduction1,2
• Adding a second antiplatelet drug (e.g.
  clopidogrel or a GPIIb/IIa antagonist) to ASA
  may produce additional benefits1

CURE results were not available at the time of
this review
1. Antithrombotic Trialists Collaboration. BMJ
2002 324 7186. 2. Antiplatelet Trialists
Collaboration. BMJ 1994 308 81106. 3. The
CURE Trial Investigators. N Engl J Med 2001
345 494502.
56
Summary

• Atherothrombosis is an extensive, progressive,
  unpredictable and deadly disease affecting the
  coronary, cerebral and peripheral circulation1
• Patients with vascular disease in one territory
  are also at high risk of further ischemic (or
  atherothrombotic) events in the other vascular
  territories2
• Antiplatelet therapy is a necessary life-long
  treatment for all patients at risk of
  atherothrombosis3
• Combining antiplatelet agents with different
  modes of action can achieve optimum benefit3
• Adding a second antiplatelet drug, such as
  clopidogrel, to ASA may produce additional
  benefits3,4

1. Nenci GG. Eur Heart J 1999 1(suppl A)
A27A30. 2. Lichtman JH et al. Circulation 2002
105 10827. 3. Antithrombotic Trialists
Collaboration. BMJ 2002 324 7186. 4. The CURE
Trial Investigators. N Engl J Med 2001 345
494502.
57
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58
Disclaimer

• This slide kit presents data to support the
  rationale for the use of ADP-receptor antagonists
  in registered and non-registered indications.
• The slide kit has been prepared for medical and
  scientific purposes, and cannot be considered as
  an inducement to use clopidogrel in
  non-registered indications.
• Neither Sanofi-Synthélabo nor Bristol-Myers
  Squibb recommends the use of clopidogrel in any
  manner inconsistent with that described in the
  full prescribing information.