Understanding Atherothrombosis

1
Understanding Atherothrombosis the REACH
Registry
2
Contents

• Atherothrombosis, a life threatening disease
• Understanding the disease definition and
  manifestations
• Epidemiology a highly prevalent disease
• Burden a significant toll on individuals and
  their communities
• Managing the constant and unpredictable risk of
  atherothrombosis
• The REACH Registry an overview

3
Understanding Atherothrombosis A Summary

• Atherothrombosis is a progressive and life-long
  condition that can affect the entire vascular
  system, with multiple manifestations1,2
• Atherothrombosis is characterized by the
  disruption (rupture, fissure, or erosion) of
  atherosclerotic plaques, which leads to platelet
  activation and blood clot (thrombus) formation1,2
• The result can be an acute event (such as MI), or
  long-term progression of vascular disease1,2
• A few things are important to understand in the
  development of the disease
• Plaque disruption is a critical first step2
• Platelets undergo important changes3
• Inflammation is a central process in
  atherothrombosis4

1. Falk E et al. Circulation 19959265767 2.
Arbustini E et al. Heart 199982269272 3.
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
4. Reape TJ, Groot PH Atherosclerosis 1999
147(2)213-25
4
Atherothrombosis Has Multiple Manifestations
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
200213(suppl 1)16
5
Atherothrombosis A Generalized And Progressive
Disease
Atherosclerosis
Unstable angina MI Ischemic stroke/TIA Critical
leg ischemia Intermittent claudication CV death
Thrombosis
ACS
Stable angina/Intermittent claudication
Adapted from Libby P. Circulation.
2001104365-372
6
Platelet Adhesion and Activation, Provoked By
Endothelial Damage
Aggregation of platelets intoa thrombus
Normal platelets in flowing blood
Platelets adhering to damaged endothelium and
undergoing activation
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 Martin
Dunitz 2000 pp.1535
7
Thrombus Formation Can Lead To Acute Events Or
Disease Progression

• Acute Events
• Acute coronary syndromes, stroke, acute limb
  ischemia

Occlusive thrombus
Plaque rupture
Platelet activation and aggregation

• Disease Progression
• Plaque growth

Non-occlusive thrombus
Healing and resolution
Adapted from Drouet L. Cerebrovasc Dis
200213(suppl 1) 16
8
Micro-embolisation Can Cause Serious
Microvascular Effects
Micro-Embolization
Plaque rupture
Microvascular obstruction

• Microemboli
• Can occur while a plaque is active, and can last
  for hours, days or weeks
• Can lead to microvascular obstruction in the
  myocardium, brain or peripheral tissues
• Results can include cardiac insufficiency or
  vascular dementia, depending on site

Adapted from Topol EJ, Yadav JS. Circulation
200010157080, and Falk E et al. Circulation
19959265771
9
Atherogenesis a Complex and Progressive Process
Pathology of Atherogenesis
Initiation Accumulation of lipids at vascular
junctions experiencing high shear forces
Inflammatory cytokines induce expression of
adhesion molecules
Macrophages bind to and enter intima wall
Macrophages become foam cells fatty streak
formed
Chemo-attractants such as PDGF released from
activated macrophages
Uptake of Lipids by Macrophages
Smooth muscle cells (SMCs) migrate into the intima
Result Atherosclerotic plaque
Adapted from P Libby, The Vascular Biology of
Atherosclerosis in Braunwald E, Zipes DP
Libby P 6th Edition, Heart Disease a Textbook
of Cardiovascular Medicine 2001 London WB
Saunders
10
Stable And Unstable Plaques Some Important
Differences
Characteristics of Stable and Unstable Plaques1

• Rupture leads to exposure of collagen and
  initiation of the physiological hemostatic
  cascade commencing with platelet adhesion and
  activation

1. Robbi L Libby P. Ann N Y Acad Sci
2001947167-79 2. Tedgui A, Mallat, Z Arch Mal
Coeur Vaiss 200396(6)671-5
11
Inflammation Plays A Key Role In The
Atherothrombotic Process
Chemokines (eg MCP-1, RANTES, IL-8)1
Monocyte recruitment into intima
Lesion Development
Inflammatory cytokines, released by many cell
types including platelets, smooth muscle cells,
lymphocytes in response to lipid flux and
endothelial damage
Adhesion molecules (eg. VCAM-1ICAM-1)
MMPs - Released by macrophages, degrade plaque
Plaque degradation rupture thrombosis
Plaque degradation rupture
Apoptosis of smooth muscle cells
12
Contents

• Atherothrombosis, a life threatening disease
• Understanding the disease definition and
  manifestations
• Epidemiology a highly prevalent disease
• Burden a significant toll on individuals and
  their communities
• Managing the constant and unpredictable risk of
  atherothrombosis
• The REACH Registry an overview

13
Epidemiology A Highly Prevalent Disease

• Atherothrombosis is a leading cause of death
  worldwide. Large numbers of people are already
  affected
• Acute events
• Ongoing morbidity
• Risk of future events
• The burden of atherothrombosis is growing

14
Atherothrombosis is a Leading Cause of Death
Worldwide1
Leading Causes Of Death, Worldwide ( of all
deaths)
0
5
10
15
20
25
30
Mortality ()
Ischemic heart disease, cerebrovascular disease,
inflammatory heart disease andhypertensive heart
disease Worldwide defined as Member States by
WHO Region (Africa, Americas,Eastern
Mediterranean, European, South-East Asia and
Western Pacific)
1. The World Health Report, 2002, WHO Geneva, 2002
15
Large Numbers of People Affected in the USA
Epidemiology Of Atherothrombotic Manifestations
In The USA
Incidence per year
Prevalence
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 2001358125764 3. Weitz JI et al.
Circulation 199694302649
16
Large numbers of people affected in Europe1
Epidemiology Of Atherothrombotic Manifestations
In Europe
Incidence (number of events per 3564 years 75
years 100,000 patients per year in 1997)
(men/women) (men/women)
Myocardial infarction
163/26
991/811
European Mediterranean countries (average)
290/86
1,666/1,327
European Nordic countries (average)
Ischemic stroke
148/51
1,486/1,264
European Mediterranean countries (average)
101/60
1,317/1,401
European Nordic countries (average)

According to patient age, sex and country of
originSpain, Italy, FranceUK, Germany,
Netherlands
1. Guillot F Moulard O. Circulation
199898(abstr suppl 1)1421
17
Contents

• Atherothrombosis, a life threatening disease
• Understanding the disease definition and
  manifestations
• Epidemiology a highly prevalent disease
• Burden a significant toll on individuals and
  their communities
• Managing the constant and unpredictable risk of
  atherothrombosis
• The REACH Registry an overview

18
The Burden of Atherothrombosis is Growing1
Projections of population 50, and prevalence of
MI Ischemic Stroke, Europe North
America(millions)
31.6
11.8
32.7
12.8
Increase since 1997
14 countries Belgium, Canada, Denmark, Finland,
France, Germany, Italy, Netherlands, Norway,
Spain, Sweden, Switzerland, UK, USA
1. Guillot F Moulard O. Circulation
199898(abstr suppl 1)1421
19
Atherothrombosis Significantly Shortens Life
Expectancy
Average remaining life expectancy at age 60 (men)
-9.2 years
-7.4 years
-12 years
20
18
16
14
12
Years
10
8
6
4
2
0
Healthy
History of CV disease
History of AMI
History of stroke
Analysis of data from the Framingham Heart
Study AMI Acute myocardial infarction
1. Peeters et al. Eur Heart J 200223458466
20
Cerebrovascular Disease Significantly Impacts
Morbidity And Mortality1
Rate of Stroke, and outcomes after Stroke
(per million inhabitants)
3000
By 1 year Dead (29) Dependent
(25) Independent (46)
2500
480
2000
220
per million inhabitants
1500
600
2400
1000
1100
500
0
Stroke patients
At 3 months
At 1 year
(first or recurrent)
Of those who have suffered a stroke or TIA, the
recurrent risk is 7 per year
1. Hankey GJ Warlow C. Lancet 1999354145763
21
Atherothrombosis Is Commonly Found in More Than
One Arterial Bed In An Individual Patient1
Cerebrovascular disease
Coronary disease
26
A total of 26 of patients had manifestations of
atherothrombosis in more than arterial bed
Peripheral arterial disease
1. Coccheri S. Eur Heart J 199819(suppl)P1268
Data from CAPRIE study (n19,185)
22
Cerebrovascular Events Strongly Influence Future
Vascular Risk
Causes of death after first-ever stroke in an
Australian population1
100
90
80
Unknown
70
60
Non-vascular
Proportion of deaths ()
50
Cardiovascular
40
30
Recurrent stroke
20
Related to first stroke
10
0
30d6m
6m1yr
13yr
35yr
Time
1. Hankey GJ. Stroke 20003120806
23
High Risk of Cardiovascular Death after Cerebral
Infarction
5-Year Mortality Risk in US Stroke Patients1
300 US patients (40 black, 34 Hispanic, 26
white) with cerebral infarction 39 year old
1. Sacco RL et al. Neurology 19944462634
24
Mortality in PAD patients is Directly Related to
Severity of Symptoms 1
Peripheral Arterial Disease (PAD) and All-Cause
Mortality in the US
1.00
Normal Subjects
0.75
Asymptomatic Large Vessel-PAD
0.50
Survival
Symptomatic Large Vessel-PAD
Severe Symptomatic Large Vessel-PAD
0.25
0.00
0
2
4
6
8
10
12
Year
Kaplan-Meier survival curves based on mortality
from all-causes
1. Criqui MH. Vasc Med 20016(suppl 1)37
25
Acute Coronary Syndrome Causes Large Numbers of
Hospitalizations in the US1
Acute coronary syndromes
1.5 million hospital admissions per year
Unstable angina (UA)
Myocardial infarction(Q-wave and non-Q-wave)
750,000 admissions
750,000 admissions
1. Cairns J et al. Can J Cardiol 199612127992
26
Contents

• Atherothrombosis, a life threatening disease
• Understanding the disease definition and
  manifestations
• Epidemiology a highly prevalent disease
• Burden a significant toll on individuals and
  their communities
• Managing the constant and unpredictable risk of
  atherothrombosis
• The REACH Registry an overview

27
Managing The Constant, Unpredictable Risk Of
Atherothrombosis

• Risk factors for atherothrombosis are well
  defined
• They include obesity, smoking, diabetes etc1
• The presence of risk factors has a significant
  effect on outcomes2
• Multiple risk factors increase the likelihood of
  atherothrombotic events1
• Many risk factors are easily assessed and
  quantifiable3,4,5,6
• Identification of high risk patients and
  management of their risk factors can lead to
  reduction of risk7

1. Yusuf S et al. Circulation 2001 2. Caro J.
Eur Heart J 200122(abstr suppl)522 3. Yusuf S
et al. Circulation 2001 4. Droste DW,
Ringelstein EB. Cerebrovasc Dis. 200213 Suppl
17-11 3. Peeters et al. Eur Heart J 2002 23
458-466 5. Grundy SM et al. Circulation
19991001481-1492 6. Sloss E et al.
Circulation 2001 Supplement II 104 (17)
Abstract 3746 7. Grundy SM et al. Circulation
19991001481-1492
28
Many Risk Factors for Atherothrombosis Are Well
Defined
Major Risk Factors for Atherothrombotic Events1,2
Major Risk Factors
Classical Risk Factors Obesity, Family , history
of CVD, Diabetes Lifestyle factors Atrial
fibrillation Homocystinemia Hyperlipidemia Hyperte
nsion Hypercoagulable states Gender Age
Atherothrombotic History Prior MI Prior
Stroke Unstable angina TIA Stable angina PAD
Emerging Risk Factors Elevated prothrombotic
factors fibrinogen, CRP, PAI-1, Decreased
ABI Elevated IMT Genetic traits
1. Grundy SM et al. Circulation
199910014811492 2. Haffner SM et al. N Engl
J Med 1998339229234
29
The Presence of Risk Factors Has Profound Effects
on Long-Term Outcomes
Estimated Increase in Risk of CHD Death Or
Non-Fatal MI () 1
Note Based on 6,595 men aged 45-64 in the United
Kingdom CHD Coronary Heart Disease
1. The West of Scotland Coronary Prevention Study
Group. Am J Cardiol 199779756-762
30
Event Rate Increases With Number of Risk Factors1
Atherothrombotic Events per year
1. Caro J. Eur Heart J 200122(abstr suppl)522
31
Diabetes and Previous MI Carry Equal Risk and
That Risk is Additive
Incidence rates of myocardial infarction in a
Finnish population (at seven years)
1. Haffner SM et al. N Engl J Med 1998
23339(4)229-34
32
Risk Factors Are Easily Identified And Can Be
Managed

• Identifying patients at risk can lead to
• Lifestyle modification and/or medical therapy to
  reduce risk and increase life expectancy3
• Aggressive modification of risk factors in high
  risk patients produces risk reductions of up to
  504
• Reduction of economic costs5

ABI ankle-brachial index
1. Yusuf S et al. Circulation 2001 2. Droste
DW, Ringelstein EB. Cerebrovasc Dis. 200213
Suppl 17-11 3. Peeters et al. Eur Heart J 2002
23 458-466 4. Grundy SM et al. Circulation
19991001481-1492 5. Sloss E et al.
Circulation 2001 Supplement II 104 (17)
Abstract 3746
33
Contents

• Atherothrombosis, a life threatening disease
• Understanding the disease definition and
  manifestations
• Epidemiology a highly prevalent disease
• Burden a significant toll on individuals and
  their communities
• Managing the constant and unpredictable risk of
  atherothrombosis
• The REACH Registry an overview

34
REACH Registry The Background

• The REACH Registry has the potential to be one of
  the largest disease registries to date
• It seeks to overcome deficiencies in our current
  knowledge of atherothrombosis in at-risk
  populations
• Evaluation of the at-risk population for
  atherothrombosis is still limited
• The Registry will include a broad range of
  at-risk subjects, and will involve long-term,
  prospective follow-up
• In so doing, it should achieve a number of
  important objectives
• Increase understanding and awareness of the
  disease
• Improve management and outcomes
• Provide data, useful at a global and local level

35
Evaluation of the at-risk population for
atherothrombosis is still limited
36
The REACH Registry will help to overcome many of
these limitations
37
REACH Registry Should Achieve a Number of
Important Objectives
Objectives and importance of REACH Registry,
38
REACH Registry Scope A Large and Far-reaching
International Survey of Atherothrombosis

• More than 50 000 subjects in 30 countries
  worldwide
• Selection of physicians and patients should
  deliver a representative sample of subjects
• Wide range of participating physicians, mainly in
  office-based settings
• A broad range of the at-risk population will be
  included
• Long-term, prospective and relevant data
  collected

39
Excellent Worldwide Representation From 30
Participating Countries
40
Selection of Physicians and Patients Will Deliver
A Representative Sample Of Subjects
Participating Physicians and Subjects Selection
and profile

• Participating Physicians
• Pre-defined at start of Registry
• Based on local practice population
• general practitioners, specialists
• Mainly office-based, some hospital representation
• Representative of
• Local environment
• Country geography

How are they selected? What is their
profile?

• Subjects
• Consecutive recruitment at each site
• Maximum per site determined at local level
  (subject to central guidelines)
• Within overall Registry timelines
• Subject to inclusion criteria
• Documented disease, or at-risk of
  atherothrombosis
• Real-life setting

41
A Broad Range Of The At-Risk Population Will Be
Included
REACH Registry Inclusion Criteria

• Documented cerebrovascular diseaseIschemic
  Stroke ortransient ischemic attack
• Documentedcoronary diseaseAngina, MI,
  angioplasty/stent/bypass
• Documented historicalor current
  intermittentclaudication associatedwith ABI 0.9

• Male ? 65 yearsor female ? 70 years
• Current smoking 15 cigarettes/day
• Type I or Type IIdiabetes
• Hypercholesterolemia
• Diabetic nephropathy
• Hypertension
• Ankle Brachial Index(ABI) rest
• Asymptomatic carotidstenosis ? 70
• Presence of at leastone carotid plaque

Must include Signed Written Informed Consent Pat
ients aged 45 years Or more
At least of four criteria
At least atherothrombotic risk
factors
1
3
42
Exclusion Criteria Are Simple And Logical
REACH Registry Exclusion Criteria
43
Long-term, Prospective and Relevant Data
Registry Timeline
Timelines are for worldwide participation local
timelines will be shorter
44

• The REACH registry is sponsored jointly by

INT.CLO.03.09.01