Coronary Artery Disease CAD: The Diagnosis Often Comes Too Late

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Coronary Artery Disease (CAD)The Diagnosis
Often Comes Too Late
(Adapted from Levy et al.) Levy D et al in
Textbook of Cardiovascular Medicine, 1998.
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Vascular Disease Scope of the Problem

• Vascular diseaseand CAD in particularis the
  leading cause of death in the US and other
  Western nations
• By 2020, cardiovascular disease will become the
  most common cause of death worldwide
• Due to the high initial mortality of vascular
  disease, the target of clinical practice must be
  aggressive risk factor management

American Heart Association?, 2000 Heart and
Stroke Statistical Update, 1999 Braunwald E, N
Engl J Med, 1997Kannel WB in Atherosclerosis
and Coronary Artery Disease, 1996.
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Atherosclerosis A Systemic Disease
From a prospective analysis of 1886 patients aged
?62 years, 810 patients were diagnosed with CAD
as defined by a documented clinical history of
MI, ECG evidence of Q-wave MI, or typical angina
without previous MI. (Adapted from Aronow et al.)
Aronow WS et al, Am J Cardiol, 1994.
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Carotid IMT Predicts Coronary Events

• (Adapted from Salonen.)

Salonen R in Risk Factors for Ultrasonographically
Assessed Common Carotid Atherosclerosis, 1991.
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Major Risk Factors for CAD
Grundy SM et al, Circulation, 1998 Grundy SM,
Circulation, 1999.
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CAD Risk Is Incremental

• (Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.
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Most Myocardial Infarctions Are Causedby
Low-Grade Stenoses
Pooled data from 4 studies Ambrose et al, 1988
Little et al, 1988 Nobuyoshi et al, 1991 and
Giroud et al, 1992.(Adapted from Falk et al.)
Falk E et al, Circulation, 1995.
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Lesion Severity A PoorPredictor of Survival
From the Coronary Artery Surgery Study (CASS) as
reported by Little et al.
Little WC et al, Clin Cardiol, 1991.
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Angiography Significant Limitations in Atheroma
Assessment

• Angiography reflects a planar, 2-dimensionalsilho
  uette of the lumen
• Remodeling
• Because angiography does not visualize thevessel
  wall, it cannot account for positive ornegative
  remodeling
• Composition
• Because angiography does not assess plaque
  composition, it cannot differentiate lipid-rich,
  more vulnerable plaques
• Postprocedure
• Due to plaque fissuring, angiography
  overestimatesthe degree of postintervention
  lumen expansion

Nissen SE et al in Restenosis After Intervention
With New Mechanical Devices, 1992 Yamashita T et
al, Progress in CardiovascularDiseases, 1999
Topol EJ et al, Circulation, 1995.
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Coronary Remodeling
Progression
Expansion overcome lumen narrows
Compensatory expansion maintains constant lumen
Normal vessel
Minimal CAD
Severe CAD
Moderate CAD
(Adapted from Glagov et al.)
Glagov et al, N Engl J Med, 1987.
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Angiography Cannot Account forCoronary Remodeling
3.1 mm
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Atheroma Morphology by Ultrasound
Soft Lipid-Laden Plaque
Hard Fibrous Plaque
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Angiography Masks Complicated Lesions
LAO
RAO
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Angiography Underestimates Diffuse Disease
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What Is the Culprit Lesion?

• 58-year-old male with chronic stable angina
• Positive stress test with small reversible
  ischemic defecton nuclear scintigraphy
• Medical Rx, but 6 weeks later
• 3-day history of unstableangina, including30
  minutes of rest pain
• Medically cooled offfollowed by angiography

Case provided by the McLaren Heart and Vascular
Center, Flint, Michigan used with permission.
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Absence of Correlation Between Angiographic
Results and Clinical Outcomes

• (Adapted from Brown et al.)

Brown BG et al, Circulation, 1993.
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Same Lumen Size Different Atheromas
Thin Cap With Lipid Core
Thick Stable Fibrotic Cap
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Assessing Volumetric Atheroma Changes

• Trial performed at Kobe General Hospital (Kobe,
  Japan)
• Hypothesis patients with angiographically normal
  arteries receiving statin therapy will show
  reduced progression of coronary plaque as
  measured by IVUS

Takagi T et al, Am J Cardiol, 1997.
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IVUS Changes in Atheroma Volume

• Statin reduced TC and LDL-C no change in HDL-C
  or TG

Results for 25 patients (13 in the pravastatin
group, 12 in the control group) who completed the
study. These patients were similarat baseline
with regard to dyslipidemia (LDL-C 200-260 mg/dL)
and IVUS. Mean plaque index at baseline was
41.2. Qualifying arteries had not undergone a
procedure and were angiographically normal (lt25
lumen reduction). (Adapted from Takagi et al.)
Takagi T et al, Am J Cardiol, 1997.
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Ongoing Statin Trials Utilizing IVUS REVERSAL

• Primary hypothesis
• A large (vs moderate) reduction in LDL-C will
  cause a greater decrease in the total
  atherosclerotic burden in patients with
  established CAD measured by IVUS
• Secondary hypothesis
• The reduction in plaque burden as assessed by
  IVUS will be evident despite the absence of any
  angiographically apparent improvement

Data on file, Pfizer Inc., New York, NY.
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REVERSAL Study Design

• International, prospective, randomized,
  multicenter, double-blind
• Projected completion 2002

Data on file, Pfizer Inc., New York, NY.
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Interventions Beyond Lipid Reduction
Lichtlen PR et al, Lancet, 1990 Waters D et al,
Circulation, 1990 Borhani NO et al, JAMA, 1996.
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CCB Imaging Trials Results

• INTACTCCB showed significantly lower rate of new
  lesions neutral effect on existing lesions
• Montreal Heart StudyCCB showed significantly
  less progression of early lesions neutral effect
  on existing lesions overall
• MIDASCCB showed initial effect on IMT but there
  was no subsequent difference
• Although these trials were not powered for
  clinical end points, the shorter-acting CCBs
  exerted neutral effects overall nonsignificant
  trends suggested poorer outcomes in at least one
  study

Lichtlen PR et al, Lancet, 1990 Waters D et al,
Circulation, 1990 Borhani NO et al, JAMA, 1996.
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Ongoing IVUS/Calcium Channel Blocker Trial
CAMELOT/NORMALISE

• CAMELOT hypothesis
• Whether amlodipine will reduce major cardiacend
  points in patients with CAD compared with
  enalapril and placebo
• NORMALISE (substudy) hypothesis
• Whether amlodipine will reduce the progression of
  coronary atherosclerosis as measured by IVUS(vs
  QCA)

Data on file, Pfizer Inc., New York, NY.
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CAMELOT/NORMALISE Study Design

• International, prospective, randomized,
  multicenter, double-blind
• Projected completion 2003

Data on file, Pfizer Inc., New York, NY.
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IVUS An Invaluable Research Tool

• Correlates more closely with clinical end points
  than angiography, which is insensitive until
  lesions are relatively advanced
• Reveals direct effects on plaque of
  treatmentsfor atherosclerosis as well as
  modifications of its predisposing risks
• Used in conjunction with angiography, IVUS is
  uncovering new data about vascular responseand
  atherogenesis

Nissen SE et al in Textbook of Cardiovascular
Medicine, 1998 Yamashita T et al, Progress in
Cardiovascular Diseases, 1999Topol EJ et al,
Circulation, 1995.
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Atherosclerosis Begins in Childhood

• (Adapted from Berenson et al.)

Berenson GS et al, N Engl J Med, 1998.
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One in Six Teenagers Has Atheromas
(Adapted from Tuzcu et al.)
Tuzcu EM et al, in press.
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Consistent Evidence of Early Atherosclerosis

• (Adapted from Berenson et al and Tuzcu et al.)

Berenson GS et al, N Engl J Med, 1998 Tuzcu EM
et al, in press.
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CAD Silent Disease Necessitates Aggressive Risk
Factor Management

• IVUS corroborates necroscopy studies, proving
  that atherosclerosis begins in youth
• CAD progresses silently the initial presentation
  is usually MI or sudden death
• Most atheromas are extraluminal, rendering them
  angiographically silent
• The only reasonable approach is early and
  aggressive risk factor management

Berenson GS et al, N Engl J Med, 1998 Tuzcu EM
et al, in press Levy D et al in Textbook of
Cardiovascular Medicine, 1998 Yamashita T et al,
Progress in Cardiovascular Diseases, 1999 Topol
EJ et al, Circulation, 1995. Kannel WB in
Atherosclerosis and Coronary Artery Disease,
1996.
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The Correlation Between Atherosclerosis and Risk
Factors Begins Early

• (Adapted from Berenson et al.)

Berenson GS et al, N Engl J Med, 1998.
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Small Increases in Cholesterol Lead to Dramatic
Increases in CAD Death

• (Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.
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CAD Not Just a Lipid Disease

• Half of all MIs occur in normolipidemic patients
• SmokingAccounts for 200,000 cardiovascular
  deaths annually
• DiabetesAffects 16 million Americansand is
  growing
• HypertensionConfers as much risk for MI as
  smoking or dyslipidemia
• Systolic hypertension is an even greater
  indicator of CAD risk than diastolic hypertension

Braunwald E, N Engl J Med, 1997 Grundy SM et al,
Circulation, 1998 The Joint National Committee
on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure and the National
High Blood Pressure Education Program
Coordinating Committee, Arch Intern Med, 1997.
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Systolic BP Confers Incremental RiskEven Within
Normal Levels

• (Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.
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CAD Risk Factors Minimal and Optimal
Grundy SM, Circulation, 1999 American Heart
Association Consensus Panel, Circulation, 1995
The Joint National Committee on Prevention,
Detection, Evaluation, and Treatment of High
Blood Pressure and the National High Blood
Pressure Education Program Coordinating
Committee, Arch Intern Med, 1997.
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Conclusions Critical Lessonsin Understanding
Atherogenesis

• CAD is a ubiquitous, systemic disease that
  requires a systemic solution
• Most patients progress to MI or sudden death
  before a diagnosis of CAD is ever considered
• IVUS demonstrates that remodeling causes
  angiography to underestimate the extent of
  disease
• Extraluminal, angiographically silent atheromas
  are responsible for most acute coronary events,
  including sudden death

Aronow WS et al, Am J Cardiol, 1994 Levy D et al
in Textbook of Cardiovascular Medicine, 1998
Nissen SE et al in Textbook of Cardiovascular
Medicine, 1998 Falk E et al, Circulation, 1995.
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Conclusions Risk Factor Management

• Atherosclerosis begins in childhood and is
  strongly associated with major CAD risk factors
  from the youngest ages
• Hypertension (particularly systolic), diabetes,
  and smokingin addition to dyslipidemiaconfer
  comparable risks
• The effect of these risk factors is continuous,
  extending even into the normal range
• Therefore, aggressive risk factor modification is
  the most effective strategy for reducing the
  consequences of CAD

Berenson GS et al, N Engl J Med, 1998 Braunwald
E, N Engl J Med, 1997 Neaton JD et al, Arch
Intern Med, 1992 Kannel WB inAtherosclerosis
and Coronary Artery Disease, 1996.
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Awaiting overt signs and symptoms of coronary
diseasebefore treatment is no longer
justified. In some respects, the occurrence of
symptoms may be regarded more properly as a
medical failure than as the initial indication
for treatment. William B. Kannel, MDDepartment
of MedicineBoston University Medical Center
Kannel WB in Atherosclerosis and Coronary Artery
Disease, 1996.
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Supplemental Slides
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Carotid DiseaseA Reliable Predictor of Coronary
Risk

• Carotid atherosclerosis, even when very mild,is
  associated with MI and sudden cardiac death
• Ultrasound-derived carotid intimal-medial
  thickness (IMT) has been shown to predict the
  risk of MI
• The same risk factors predispose patients to
  atherosclerosis in both the coronary and carotid
  arterial systems

Salonen R in Risk Factors for Ultrasonographically
Assessed Common Carotid Atherosclerosis, 1991
OLeary DH et al, N Engl J Med, 1999 Androulakis
AE et al, Eur Heart J, 2000.
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Emerging Risk Factors

• Increased serum homocysteine
• Increased lipoprotein (a) (Lpa)
• Increased C-reactive protein (CRP)
• Chlamydia pneumoniae infection
• Estrogen deficiency
• Coagulation factor abnormalities
• Plasma fibrinogen
• Factor VII
• Endogenous tissue plasminogen activator
• Plasminogen-activator inhibitor type I
• D-Dimer

Braunwald E, N Engl J Med, 1997.
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Multiple Risk Factors Additive Risk
Risk of developing CAD over 10 years according to
specified BP levels and other risk factors.
Calculations are based on a Framingham Heart
Study computer program, which includes variables
for systolic BP, diastolic BP, TC, HDL-C, LVH by
ECG, cigarette smoking, and glucose intolerance.
The following remained constant unless otherwise
indicated male, age 45 years, TC 180 mg/dL, HDL
45, and nonsmoker. Elevated LDL-C estimated based
on TC 250 mg/dL with triglycerides 200 mg/dL.
(Data on file, Pfizer Inc.)
Grundy SM et al, J Am Coll Cardiol, 1999 Data on
file, Pfizer Inc., New York, NY.
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Angiography UnderestimatesDiffuse Disease
Nissen SE et al in Textbook of Cardiovascular
Medicine, 1998 Topol EJ et al, Circulation, 1995.
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An Apparently Successful Angioplasty
Postintervention
Preintervention
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A
B
C
D
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Angiography Has Major Limitationsin Assessing
Complicated Lesions
Nissen SE et al in Textbook of Cardiovascular
Medicine, 1998 Topol EJ et al, Circulation, 1995.
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Precision Cross-Sectional Planimetry
Direct and Calculated Atheroma Measurements
EEM 15.47 mm2
Lumen 5.51 mm2
Atheroma Area 9.96 mm2 Area Reduction 64.4
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Atheroma Morphology by Ultrasound
Moderate Calcification
Severe Calcification
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Morphology of Ruptured Atheroma
Fibrous Cap Fracture With Escape of Lipid Core
Missing Lipid Core
Fracture Site
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ENCORE A CCB/Statin IVUS Trial

• ENCORE I hypothesis CCB and/or statin therapy
  will improve coronary endothelial function in CAD
  patients
• Prospective, randomized, double-blind (completed
  2/00 results TBA)

Lüscher TF et al, Eur Heart J Supplements, 2000.
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ENCORE II IVUS and Endothelial Function

• Hypothesis endothelial function improved by
  statin therapy CCBwill correlate with atheroma
  regression as measured by IVUS
• Prospective, randomized, double-blind
• Projected completion 2002

Lüscher TF et al, Eur Heart J Supplements, 2000.
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Limitations of IVUS

• Visualizes only one artery at a time
• Only arteries capable of accommodating theIVUS
  catheter may be examined
• May be distorted
• Delineates thickness and echogenicity but not
  actual histology
• More costly than angiography (although its
  benefits may be cost-effective)

Yamashita T et al, Progress in Cardiovascular
Diseases, 1999 Topol EJ et al, Circulation,
1995 Nissen SE et al, Circulation, in press.
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Other Emerging Imaging Modalities

• Angioscopy uses visible light via fiberoptic
  filaments
• Allows direct examination of surface
  characteristics and intraluminal morphology
• Doppler uses a catheter device to measure the
  velocity of red blood cells and identify flow
  patterns
• FFR (fractional flow reserve) uses a
  nonobstructive catheter to measure flow after
  maximum vasodilation
• Compares the maximum flow of a stenotic vessel
  with the same vessel without stenosis
• MRI (magnetic resonance imaging) allows
  noninvasive imaging of the cardiovascular system
• MRI may be used to investigate coronary blood
  flow but the direct analysis of atheroma remains
  unlikely

Nissen SE et al in Textbook of Cardiovascular
Medicine, 1998 White RD in Textbook of
Cardiovascular Medicine, 1998.
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Diabetes Half of All PatientsAre Unaware of
Their Condition

• CAD is the leading cause of hospitalization and
  death among patients with type 2 diabetes (NIDDM)
• Patients with both type 1 and type 2 diabetes are
  at a high short-term risk of CAD-related end
  points
• Insulin resistance increases risk and may exist
  for 25 years or more before diabetes is diagnosed
• Patients with diabetes tend to cluster other risk
  factors (such as hypertension and dyslipidemia)
  while diabetes confers risk unto itself

Aronson D et al in Atherosclerosis and Coronary
Artery Disease, 1996 Grundy SM et al, J Am Coll
Cardiol, 1999.
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UKPDS The Case for AggressiveBlood Pressure
Control
UK Prospective Diabetes Study Group.

• Mean final BP More-aggressive control, 144/82 mm
  Hg Less-aggressive control, 154/87 mm Hg

UK Prospective Diabetes Study Group, BMJ, 1998.