Coronary Artery Disease (CAD):Coronary Artery Disease (CAD):The Diagnosis Often Comes Too LateThe Diagnosis Often Comes Too Late

Coronary Artery Disease (CAD):Coronary Artery Disease (CAD):The Diagnosis Often Comes Too LateThe Diagnosis Often Comes Too Late

(Adapted from Levy et al.)(Adapted from Levy et al.)

Levy D et al in Levy D et al in Textbook of Cardiovascular MedicineTextbook of Cardiovascular Medicine, 1998., 1998.

American Heart Association, 2000 Heart and Stroke Statistical Update, 1999; Braunwald E, N Engl J Med, 1997;Kannel WB in Atherosclerosis and Coronary Artery Disease, 1996.

Vascular Disease: Scope of the ProblemVascular Disease: Scope of the ProblemVascular Disease: Scope of the ProblemVascular Disease: Scope of the Problem

• Vascular disease—and CAD in particular—Vascular disease—and CAD in particular—is the leading cause of death in the US and other is the leading cause of death in the US and other Western nationsWestern nations

• By 2020, cardiovascular disease will become the By 2020, cardiovascular disease will become the most common cause of death worldwidemost common cause of death worldwide

• Due to the high initial mortality of vascular disease, Due to the high initial mortality of vascular disease, the target of clinical practice must be aggressive the target of clinical practice must be aggressive risk factor managementrisk factor management

• Vascular disease—and CAD in particular—Vascular disease—and CAD in particular—is the leading cause of death in the US and other is the leading cause of death in the US and other Western nationsWestern nations

• By 2020, cardiovascular disease will become the By 2020, cardiovascular disease will become the most common cause of death worldwidemost common cause of death worldwide

• Due to the high initial mortality of vascular disease, Due to the high initial mortality of vascular disease, the target of clinical practice must be aggressive the target of clinical practice must be aggressive risk factor managementrisk factor management

Atherosclerosis: A Systemic DiseaseAtherosclerosis: A Systemic DiseaseAtherosclerosis: A Systemic DiseaseAtherosclerosis: A Systemic Disease

Aronow WS et al, Am J Cardiol, 1994.

From a prospective analysis of 1886 patients aged 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, 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.)ECG evidence of Q-wave MI, or typical angina without previous MI. (Adapted from Aronow et al.)

(Adapted from Salonen.)(Adapted from Salonen.)(Adapted from Salonen.)(Adapted from Salonen.)

Salonen R in Risk Factors for Ultrasonographically Assessed Common Carotid Atherosclerosis, 1991.

Carotid IMT Predicts Coronary EventsCarotid IMT Predicts Coronary EventsCarotid IMT Predicts Coronary EventsCarotid IMT Predicts Coronary Events

Major Risk Factors for CADMajor Risk Factors for CADMajor Risk Factors for CADMajor Risk Factors for CAD

Grundy SM et al, Circulation, 1998; Grundy SM, Circulation, 1999.

CAD Risk Is IncrementalCAD Risk Is IncrementalCAD Risk Is IncrementalCAD Risk Is Incremental

(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.

Most Myocardial Infarctions Are CausedMost Myocardial Infarctions Are Causedby Low-Grade Stenosesby Low-Grade Stenoses

Most Myocardial Infarctions Are CausedMost Myocardial Infarctions Are Causedby Low-Grade Stenosesby 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.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.)(Adapted from Falk et al.)

Falk E et al, Circulation, 1995.

Lesion Severity: A PoorLesion Severity: A PoorPredictor of SurvivalPredictor of Survival

Lesion Severity: A PoorLesion Severity: A PoorPredictor of SurvivalPredictor of Survival

From the Coronary Artery Surgery Study (CASS) as reported by Little et al.From the Coronary Artery Surgery Study (CASS) as reported by Little et al.

Little WC et al, Clin Cardiol, 1991.

Angiography: Significant Limitations in Angiography: Significant Limitations in Atheroma AssessmentAtheroma Assessment

Angiography: Significant Limitations in Angiography: Significant Limitations in Atheroma AssessmentAtheroma Assessment

• Angiography reflects a planar, 2-dimensionalAngiography reflects a planar, 2-dimensionalsilhouette of the lumensilhouette of the lumen

• RemodelingRemodeling–Because angiography does not visualize theBecause angiography does not visualize the

vessel wall, it cannot account for positive orvessel wall, it cannot account for positive ornegative remodelingnegative remodeling

• CompositionComposition–BecauseBecause angiography does not assess plaque angiography does not assess plaque

composition, it cannot differentiate lipid-rich, more composition, it cannot differentiate lipid-rich, more vulnerable plaquesvulnerable plaques

• PostprocedurePostprocedure–Due to plaque fissuring, angiography overestimatesDue to plaque fissuring, angiography overestimates

the degree of postintervention lumen expansionthe degree of postintervention lumen expansion

• Angiography reflects a planar, 2-dimensionalAngiography reflects a planar, 2-dimensionalsilhouette of the lumensilhouette of the lumen

• RemodelingRemodeling–Because angiography does not visualize theBecause angiography does not visualize the

vessel wall, it cannot account for positive orvessel wall, it cannot account for positive ornegative remodelingnegative remodeling

• CompositionComposition–BecauseBecause angiography does not assess plaque angiography does not assess plaque

composition, it cannot differentiate lipid-rich, more composition, it cannot differentiate lipid-rich, more vulnerable plaquesvulnerable plaques

• PostprocedurePostprocedure–Due to plaque fissuring, angiography overestimatesDue to plaque fissuring, angiography overestimates

the degree of postintervention lumen expansionthe degree of postintervention lumen expansionNissen 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.

(Adapted from Glagov et al.)(Adapted from Glagov et al.)

Coronary RemodelingCoronary RemodelingCoronary RemodelingCoronary Remodeling

NormalNormalvesselvessel

MinimalMinimalCADCAD

ProgressionProgression

Compensatory expansionCompensatory expansionmaintains constant lumenmaintains constant lumen

Expansion Expansion overcome:overcome:

lumen narrowslumen narrows

SevereSevereCADCAD

ModerateModerateCADCAD

Glagov et al, Glagov et al, N Engl J MedN Engl J Med, 1987., 1987.

3.1 mm3.1 mm

3.1 mm3.1 mm

Angiography Cannot Account forAngiography Cannot Account forCoronary RemodelingCoronary Remodeling

Atheroma Morphology by UltrasoundAtheroma Morphology by Ultrasound

““Soft” Lipid-Laden PlaqueSoft” Lipid-Laden Plaque““Soft” Lipid-Laden PlaqueSoft” Lipid-Laden Plaque ““Hard” Fibrous PlaqueHard” Fibrous Plaque““Hard” Fibrous PlaqueHard” Fibrous Plaque

LAO RAO

Angiography Masks Complicated LesionsAngiography Masks Complicated Lesions

Angiography Underestimates Diffuse DiseaseAngiography Underestimates Diffuse Disease

What Is the Culprit Lesion?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 off”followed by angiography

• 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 off”followed by angiography

Case provided by the McLaren Heart and Vascular Center, Flint, Michigan; used with permission.

Absence of Correlation Between Angiographic Absence of Correlation Between Angiographic Results and Clinical OutcomesResults and Clinical Outcomes

Absence of Correlation Between Angiographic Absence of Correlation Between Angiographic Results and Clinical OutcomesResults and Clinical Outcomes

(Adapted from Brown et al.)(Adapted from Brown et al.) (Adapted from Brown et al.)(Adapted from Brown et al.)

Brown BG et al, Circulation, 1993.

Thin Cap With Lipid CoreThin Cap With Lipid CoreThin Cap With Lipid CoreThin Cap With Lipid Core Thick Stable Fibrotic CapThick Stable Fibrotic CapThick Stable Fibrotic CapThick Stable Fibrotic Cap

Same Lumen Size: Different AtheromasSame Lumen Size: Different Atheromas

Assessing Volumetric Atheroma ChangesAssessing Volumetric Atheroma ChangesAssessing Volumetric Atheroma ChangesAssessing Volumetric Atheroma Changes• Trial performed at Kobe General Hospital (Kobe, Japan)Trial performed at Kobe General Hospital (Kobe, Japan)• Hypothesis: patients with angiographically normal arteries Hypothesis: patients with angiographically normal arteries

receiving statin therapy will show reduced progression of receiving statin therapy will show reduced progression of coronary plaque as measured by IVUScoronary plaque as measured by IVUS

• Trial performed at Kobe General Hospital (Kobe, Japan)Trial performed at Kobe General Hospital (Kobe, Japan)• Hypothesis: patients with angiographically normal arteries Hypothesis: patients with angiographically normal arteries

receiving statin therapy will show reduced progression of receiving statin therapy will show reduced progression of coronary plaque as measured by IVUScoronary plaque as measured by IVUS

Takagi T et al, Am J Cardiol, 1997.

IVUS: Changes in Atheroma VolumeIVUS: Changes in Atheroma VolumeIVUS: Changes in Atheroma VolumeIVUS: Changes in Atheroma Volume

Results for 25 patients (13 in the pravastatin group, 12 in the control group) who completed the study. These patients were similarResults 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 at 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 (<25% lumen reduction). (Adapted from Takagi et al.)not undergone a procedure and were angiographically normal (<25% lumen reduction). (Adapted from Takagi et al.)

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

Takagi T et al, Am J Cardiol, 1997.

Ongoing Statin Trials Utilizing IVUS: Ongoing Statin Trials Utilizing IVUS: REVERSALREVERSAL

Ongoing Statin Trials Utilizing IVUS: Ongoing Statin Trials Utilizing IVUS: REVERSALREVERSAL

Primary hypothesisPrimary hypothesis• A large (vs moderate) reduction in LDL-C will cause A large (vs moderate) reduction in LDL-C will cause

a greater decrease in the total atherosclerotic a greater decrease in the total atherosclerotic burden in patients with established CAD measured burden in patients with established CAD measured by IVUSby IVUS

Secondary hypothesisSecondary hypothesis• The reduction in plaque burden as assessed by The reduction in plaque burden as assessed by

IVUS will be evident despite the absence of any IVUS will be evident despite the absence of any angiographically apparent improvementangiographically apparent improvement

Primary hypothesisPrimary hypothesis• A large (vs moderate) reduction in LDL-C will cause A large (vs moderate) reduction in LDL-C will cause

a greater decrease in the total atherosclerotic a greater decrease in the total atherosclerotic burden in patients with established CAD measured burden in patients with established CAD measured by IVUSby IVUS

Secondary hypothesisSecondary hypothesis• The reduction in plaque burden as assessed by The reduction in plaque burden as assessed by

IVUS will be evident despite the absence of any IVUS will be evident despite the absence of any angiographically apparent improvementangiographically apparent improvement

Data on file, Pfizer Inc., New York, NY.

REVERSAL: Study DesignREVERSAL: Study DesignREVERSAL: Study DesignREVERSAL: Study Design• International, prospective, randomized, multicenter, double-blindInternational, prospective, randomized, multicenter, double-blind• Projected completion: 2002Projected completion: 2002• International, prospective, randomized, multicenter, double-blindInternational, prospective, randomized, multicenter, double-blind• Projected completion: 2002Projected completion: 2002

Data on file, Pfizer Inc., New York, NY.

Interventions Beyond Lipid ReductionInterventions Beyond Lipid ReductionInterventions Beyond Lipid ReductionInterventions Beyond Lipid Reduction

Lichtlen PR et al, Lancet, 1990; Waters D et al, Circulation, 1990; Borhani NO et al, JAMA, 1996.

CCB Imaging Trials: ResultsCCB Imaging Trials: ResultsCCB Imaging Trials: ResultsCCB Imaging Trials: Results

• INTACTINTACT–CCB showed significantly lower rate of new lesions; neutral –CCB showed significantly lower rate of new lesions; neutral effect on existing lesionseffect on existing lesions

• Montreal Heart StudyMontreal Heart Study–CCB showed significantly less progression of –CCB showed significantly less progression of early lesions; neutral effect on existing lesions overallearly lesions; neutral effect on existing lesions overall

• MIDASMIDAS–CCB showed initial effect on IMT; but there was no subsequent –CCB showed initial effect on IMT; but there was no subsequent differencedifference

• Although these trials were not powered for clinical end points, the Although these trials were not powered for clinical end points, the shorter-acting CCBs exerted neutral effects overall; nonsignificant shorter-acting CCBs exerted neutral effects overall; nonsignificant trends suggested poorer outcomes in at least one study trends suggested poorer outcomes in at least one study

• INTACTINTACT–CCB showed significantly lower rate of new lesions; neutral –CCB showed significantly lower rate of new lesions; neutral effect on existing lesionseffect on existing lesions

• Montreal Heart StudyMontreal Heart Study–CCB showed significantly less progression of –CCB showed significantly less progression of early lesions; neutral effect on existing lesions overallearly lesions; neutral effect on existing lesions overall

• MIDASMIDAS–CCB showed initial effect on IMT; but there was no subsequent –CCB showed initial effect on IMT; but there was no subsequent differencedifference

• Although these trials were not powered for clinical end points, the Although these trials were not powered for clinical end points, the shorter-acting CCBs exerted neutral effects overall; nonsignificant shorter-acting CCBs exerted neutral effects overall; nonsignificant trends suggested poorer outcomes in at least one study 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.

Ongoing IVUS/Calcium Channel Blocker Ongoing IVUS/Calcium Channel Blocker Trial: CAMELOT/NORMALISETrial: CAMELOT/NORMALISE

Ongoing IVUS/Calcium Channel Blocker Ongoing IVUS/Calcium Channel Blocker Trial: CAMELOT/NORMALISETrial: CAMELOT/NORMALISE

CAMELOT hypothesisCAMELOT hypothesis• Whether amlodipine will reduce major cardiacWhether amlodipine will reduce major cardiac

end points in patients with CAD compared with end points in patients with CAD compared with enalapril and placeboenalapril and placebo

NORMALISE (substudy) hypothesisNORMALISE (substudy) hypothesis• Whether amlodipine will reduce the progression of Whether amlodipine will reduce the progression of

coronary atherosclerosis as measured by IVUScoronary atherosclerosis as measured by IVUS(vs QCA)(vs QCA)

CAMELOT hypothesisCAMELOT hypothesis• Whether amlodipine will reduce major cardiacWhether amlodipine will reduce major cardiac

end points in patients with CAD compared with end points in patients with CAD compared with enalapril and placeboenalapril and placebo

NORMALISE (substudy) hypothesisNORMALISE (substudy) hypothesis• Whether amlodipine will reduce the progression of Whether amlodipine will reduce the progression of

coronary atherosclerosis as measured by IVUScoronary atherosclerosis as measured by IVUS(vs QCA)(vs QCA)

Data on file, Pfizer Inc., New York, NY.

CAMELOT/NORMALISE: Study DesignCAMELOT/NORMALISE: Study DesignCAMELOT/NORMALISE: Study DesignCAMELOT/NORMALISE: Study Design• International, prospective, randomized, multicenter, double-blindInternational, prospective, randomized, multicenter, double-blind• Projected completion: 2003Projected completion: 2003• International, prospective, randomized, multicenter, double-blindInternational, prospective, randomized, multicenter, double-blind• Projected completion: 2003Projected completion: 2003

Data on file, Pfizer Inc., New York, NY.

IVUS: An Invaluable Research ToolIVUS: An Invaluable Research ToolIVUS: An Invaluable Research ToolIVUS: An Invaluable Research Tool

• Correlates more closely with clinical end points Correlates more closely with clinical end points than angiography, which is insensitive until lesions than angiography, which is insensitive until lesions are relatively advancedare relatively advanced

• Reveals direct effects on plaque of treatmentsReveals direct effects on plaque of treatmentsfor atherosclerosis as well as modifications of its for atherosclerosis as well as modifications of its predisposing risks predisposing risks

• Used in conjunction with angiography, IVUS is Used in conjunction with angiography, IVUS is uncovering new data about vascular responseuncovering new data about vascular responseand atherogenesisand atherogenesis

• Correlates more closely with clinical end points Correlates more closely with clinical end points than angiography, which is insensitive until lesions than angiography, which is insensitive until lesions are relatively advancedare relatively advanced

• Reveals direct effects on plaque of treatmentsReveals direct effects on plaque of treatmentsfor atherosclerosis as well as modifications of its for atherosclerosis as well as modifications of its predisposing risks predisposing risks

• Used in conjunction with angiography, IVUS is Used in conjunction with angiography, IVUS is uncovering new data about vascular responseuncovering new data about vascular responseand atherogenesisand atherogenesis

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

Atherosclerosis Begins in ChildhoodAtherosclerosis Begins in ChildhoodAtherosclerosis Begins in ChildhoodAtherosclerosis Begins in Childhood

(Adapted from Berenson et al.)(Adapted from Berenson et al.)(Adapted from Berenson et al.)(Adapted from Berenson et al.)

Berenson GS et al, N Engl J Med, 1998.

Tuzcu EM et al, in press.

One in Six Teenagers Has AtheromasOne in Six Teenagers Has AtheromasOne in Six Teenagers Has AtheromasOne in Six Teenagers Has Atheromas

(Adapted from Tuzcu et al.)(Adapted from Tuzcu et al.)(Adapted from Tuzcu et al.)(Adapted from Tuzcu et al.)

Consistent Evidence of Early Consistent Evidence of Early AtherosclerosisAtherosclerosis

Consistent Evidence of Early Consistent Evidence of Early AtherosclerosisAtherosclerosis

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

Berenson GS et al, N Engl J Med, 1998; Tuzcu EM et al, in press.

CAD: Silent Disease Necessitates CAD: Silent Disease Necessitates Aggressive Risk Factor ManagementAggressive Risk Factor Management

CAD: Silent Disease Necessitates CAD: Silent Disease Necessitates Aggressive Risk Factor ManagementAggressive Risk Factor Management

• IVUS corroborates necroscopy studies, proving that IVUS corroborates necroscopy studies, proving that atherosclerosis begins in youthatherosclerosis begins in youth

• CAD progresses silently; the initial presentation is CAD progresses silently; the initial presentation is usually MI or sudden deathusually MI or sudden death

• Most atheromas are extraluminal, rendering them Most atheromas are extraluminal, rendering them angiographically silentangiographically silent

• The only reasonable approach is early and The only reasonable approach is early and aggressive risk factor managementaggressive risk factor management

• IVUS corroborates necroscopy studies, proving that IVUS corroborates necroscopy studies, proving that atherosclerosis begins in youthatherosclerosis begins in youth

• CAD progresses silently; the initial presentation is CAD progresses silently; the initial presentation is usually MI or sudden deathusually MI or sudden death

• Most atheromas are extraluminal, rendering them Most atheromas are extraluminal, rendering them angiographically silentangiographically silent

• The only reasonable approach is early and The only reasonable approach is early and aggressive risk factor managementaggressive 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.

The Correlation Between Atherosclerosis The Correlation Between Atherosclerosis and Risk Factors Begins Early and Risk Factors Begins Early

The Correlation Between Atherosclerosis The Correlation Between Atherosclerosis and Risk Factors Begins Early and Risk Factors Begins Early

(Adapted from Berenson et al.)(Adapted from Berenson et al.)(Adapted from Berenson et al.)(Adapted from Berenson et al.)

Berenson GS et al, N Engl J Med, 1998.

Small Increases in Cholesterol Lead to Small Increases in Cholesterol Lead to Dramatic Increases in CAD DeathDramatic Increases in CAD Death

Small Increases in Cholesterol Lead to Small Increases in Cholesterol Lead to Dramatic Increases in CAD DeathDramatic Increases in CAD Death

(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.

CAD: Not Just a Lipid DiseaseCAD: Not Just a Lipid DiseaseCAD: Not Just a Lipid DiseaseCAD: Not Just a Lipid Disease

• Half of all MIs occur in normolipidemic patientsHalf of all MIs occur in normolipidemic patients

• SmokingSmokingAccounts for 200,000 cardiovascular deaths Accounts for 200,000 cardiovascular deaths annuallyannually

• DiabetesDiabetesAffects 16 million Americans—and is growingAffects 16 million Americans—and is growing

• HypertensionHypertensionConfers as much risk for MI as smoking or Confers as much risk for MI as smoking or dyslipidemiadyslipidemia– Systolic hypertensionSystolic hypertension is an even greater indicator of is an even greater indicator of

CAD risk than diastolic hypertensionCAD risk than diastolic hypertension

• Half of all MIs occur in normolipidemic patientsHalf of all MIs occur in normolipidemic patients

• SmokingSmokingAccounts for 200,000 cardiovascular deaths Accounts for 200,000 cardiovascular deaths annuallyannually

• DiabetesDiabetesAffects 16 million Americans—and is growingAffects 16 million Americans—and is growing

• HypertensionHypertensionConfers as much risk for MI as smoking or Confers as much risk for MI as smoking or dyslipidemiadyslipidemia– Systolic hypertensionSystolic hypertension is an even greater indicator of is an even greater indicator of

CAD risk than diastolic hypertensionCAD 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.

Systolic BP Confers Incremental RiskSystolic BP Confers Incremental RiskEven Within “Normal” LevelsEven Within “Normal” Levels

Systolic BP Confers Incremental RiskSystolic BP Confers Incremental RiskEven Within “Normal” LevelsEven Within “Normal” Levels

(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)(Adapted from Neaton et al.)

Neaton JD et al, Arch Intern Med, 1992.

CAD Risk Factors: Minimal and OptimalCAD Risk Factors: Minimal and OptimalCAD Risk Factors: Minimal and OptimalCAD 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.

Conclusions: Critical LessonsConclusions: Critical Lessonsin Understanding Atherogenesisin Understanding Atherogenesis

Conclusions: Critical LessonsConclusions: Critical Lessonsin Understanding Atherogenesisin Understanding Atherogenesis

• CAD is a ubiquitous, systemic disease that requires CAD is a ubiquitous, systemic disease that requires a systemic solutiona systemic solution

• Most patients progress to MI or sudden death Most patients progress to MI or sudden death before a diagnosis of CAD is ever consideredbefore a diagnosis of CAD is ever considered

• IVUS demonstrates that remodeling causes IVUS demonstrates that remodeling causes angiography to underestimate the extent of diseaseangiography to underestimate the extent of disease

• Extraluminal, angiographically silent atheromas are Extraluminal, angiographically silent atheromas are responsible for most acute coronary events, responsible for most acute coronary events, including sudden deathincluding sudden death

• CAD is a ubiquitous, systemic disease that requires CAD is a ubiquitous, systemic disease that requires a systemic solutiona systemic solution

• Most patients progress to MI or sudden death Most patients progress to MI or sudden death before a diagnosis of CAD is ever consideredbefore a diagnosis of CAD is ever considered

• IVUS demonstrates that remodeling causes IVUS demonstrates that remodeling causes angiography to underestimate the extent of diseaseangiography to underestimate the extent of disease

• Extraluminal, angiographically silent atheromas are Extraluminal, angiographically silent atheromas are responsible for most acute coronary events, responsible for most acute coronary events, including sudden deathincluding 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.

Conclusions: Risk Factor ManagementConclusions: Risk Factor ManagementConclusions: Risk Factor ManagementConclusions: Risk Factor Management

• Atherosclerosis begins in childhood and is strongly Atherosclerosis begins in childhood and is strongly associated with major CAD risk factors from the associated with major CAD risk factors from the youngest agesyoungest ages

• Hypertension (particularly systolic), diabetes, and Hypertension (particularly systolic), diabetes, and smoking—in addition to dyslipidemia—confer smoking—in addition to dyslipidemia—confer comparable risks comparable risks

• The effect of these risk factors is The effect of these risk factors is continuouscontinuous, , extending even into the “normal” rangeextending even into the “normal” range

• Therefore, aggressive risk factor modification is the Therefore, aggressive risk factor modification is the most effective strategy for reducing the most effective strategy for reducing the consequences of CADconsequences of CAD

• Atherosclerosis begins in childhood and is strongly Atherosclerosis begins in childhood and is strongly associated with major CAD risk factors from the associated with major CAD risk factors from the youngest agesyoungest ages

• Hypertension (particularly systolic), diabetes, and Hypertension (particularly systolic), diabetes, and smoking—in addition to dyslipidemia—confer smoking—in addition to dyslipidemia—confer comparable risks comparable risks

• The effect of these risk factors is The effect of these risk factors is continuouscontinuous, , extending even into the “normal” rangeextending even into the “normal” range

• Therefore, aggressive risk factor modification is the Therefore, aggressive risk factor modification is the most effective strategy for reducing the most effective strategy for reducing the consequences of CADconsequences 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.

“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

“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.

Supplemental SlidesSupplemental SlidesSupplemental SlidesSupplemental Slides

Carotid Disease:Carotid Disease:A Reliable Predictor of Coronary RiskA Reliable Predictor of Coronary Risk

Carotid Disease:Carotid Disease:A Reliable Predictor of Coronary RiskA Reliable Predictor of Coronary Risk

• Carotid atherosclerosis, even when very mild,Carotid atherosclerosis, even when very mild,is associated with MI and sudden cardiac deathis associated with MI and sudden cardiac death

• Ultrasound-derived carotid intimal-medial thickness Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI(IMT) has been shown to predict the risk of MI

• The same risk factors predispose patients to The same risk factors predispose patients to atherosclerosis in atherosclerosis in bothboth the coronary and carotid the coronary and carotid arterial systemsarterial systems

• Carotid atherosclerosis, even when very mild,Carotid atherosclerosis, even when very mild,is associated with MI and sudden cardiac deathis associated with MI and sudden cardiac death

• Ultrasound-derived carotid intimal-medial thickness Ultrasound-derived carotid intimal-medial thickness (IMT) has been shown to predict the risk of MI(IMT) has been shown to predict the risk of MI

• The same risk factors predispose patients to The same risk factors predispose patients to atherosclerosis in atherosclerosis in bothboth the coronary and carotid the coronary and carotid arterial systemsarterial systems

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

Emerging Risk FactorsEmerging Risk FactorsEmerging Risk FactorsEmerging Risk Factors

• Increased serum homocysteineIncreased serum homocysteine• Increased lipoprotein (a) (Lp[a])Increased lipoprotein (a) (Lp[a])• Increased C-reactive protein (CRP)Increased C-reactive protein (CRP)• Chlamydia pneumoniaeChlamydia pneumoniae infection infection• Estrogen deficiencyEstrogen deficiency• Coagulation factor abnormalitiesCoagulation factor abnormalities

– Plasma fibrinogenPlasma fibrinogen– Factor VIIFactor VII– Endogenous tissue plasminogen activatorEndogenous tissue plasminogen activator– Plasminogen-activator inhibitor type IPlasminogen-activator inhibitor type I– DD-Dimer-Dimer

• Increased serum homocysteineIncreased serum homocysteine• Increased lipoprotein (a) (Lp[a])Increased lipoprotein (a) (Lp[a])• Increased C-reactive protein (CRP)Increased C-reactive protein (CRP)• Chlamydia pneumoniaeChlamydia pneumoniae infection infection• Estrogen deficiencyEstrogen deficiency• Coagulation factor abnormalitiesCoagulation factor abnormalities

– Plasma fibrinogenPlasma fibrinogen– Factor VIIFactor VII– Endogenous tissue plasminogen activatorEndogenous tissue plasminogen activator– Plasminogen-activator inhibitor type IPlasminogen-activator inhibitor type I– DD-Dimer-Dimer

Braunwald E, N Engl J Med, 1997.

Multiple Risk Factors: Additive RiskMultiple Risk Factors: Additive RiskMultiple Risk Factors: Additive RiskMultiple Risk Factors: Additive Risk

Grundy SM et al, J Am Coll Cardiol, 1999; Data on file, Pfizer Inc., New York, NY.

Risk of developing CAD over 10 years according to specified BP levels and other risk factors. Calculations are based on a Framingham 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 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 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.)nonsmoker. Elevated LDL-C estimated based on TC 250 mg/dL with triglycerides 200 mg/dL. (Data on file, Pfizer Inc.)

Angiography UnderestimatesAngiography UnderestimatesDiffuse DiseaseDiffuse Disease

Angiography UnderestimatesAngiography UnderestimatesDiffuse DiseaseDiffuse Disease

Nissen SE et al in Textbook of Cardiovascular Medicine, 1998; Topol EJ et al, Circulation, 1995.

An Apparently Successful Angioplasty An Apparently Successful Angioplasty

PreinterventionPreinterventionPreinterventionPreintervention PostinterventionPostinterventionPostinterventionPostintervention

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Angiography Has Major LimitationsAngiography Has Major Limitationsin Assessing Complicated Lesionsin Assessing Complicated LesionsAngiography Has Major LimitationsAngiography Has Major Limitationsin Assessing Complicated Lesionsin Assessing Complicated Lesions

Nissen SE et al in Textbook of Cardiovascular Medicine, 1998; Topol EJ et al, Circulation, 1995.

Precision Cross-Sectional PlanimetryPrecision Cross-Sectional PlanimetryPrecision Cross-Sectional PlanimetryPrecision Cross-Sectional Planimetry

LumenLumen5.51 mm5.51 mm22

Direct and Calculated Atheroma MeasurementsDirect and Calculated Atheroma Measurements

EEM — 15.47 mmEEM — 15.47 mm22

Atheroma Area — 9.96 mmAtheroma Area — 9.96 mm22

Area Reduction — 64.4%Area Reduction — 64.4%

Atheroma Morphology by UltrasoundAtheroma Morphology by Ultrasound

Moderate CalcificationModerate CalcificationModerate CalcificationModerate Calcification Severe CalcificationSevere CalcificationSevere CalcificationSevere Calcification

Morphology of Ruptured Atheroma Morphology of Ruptured Atheroma Morphology of Ruptured Atheroma Morphology of Ruptured Atheroma

Fibrous Cap Fracture With “Escape” of Lipid CoreFibrous Cap Fracture With “Escape” of Lipid CoreFibrous Cap Fracture With “Escape” of Lipid CoreFibrous Cap Fracture With “Escape” of Lipid Core

Fracture Site

Fracture Site

“Missing” Lipid Core

“Missing” Lipid Core

ENCORE: A CCB/Statin IVUS TrialENCORE: A CCB/Statin IVUS TrialENCORE: A CCB/Statin IVUS TrialENCORE: A CCB/Statin IVUS Trial

Lüscher TF et al, Eur Heart J Supplements, 2000.

• ENCORE I hypothesis: CCB and/or statin therapy will improve coronary ENCORE I hypothesis: CCB and/or statin therapy will improve coronary endothelial function in CAD patientsendothelial function in CAD patients

• Prospective, randomized, double-blind (completed 2/00; results TBA)Prospective, randomized, double-blind (completed 2/00; results TBA)

• ENCORE I hypothesis: CCB and/or statin therapy will improve coronary ENCORE I hypothesis: CCB and/or statin therapy will improve coronary endothelial function in CAD patientsendothelial function in CAD patients

• Prospective, randomized, double-blind (completed 2/00; results TBA)Prospective, randomized, double-blind (completed 2/00; results TBA)

• Hypothesis: endothelial function improved by statin therapy ±CCBHypothesis: endothelial function improved by statin therapy ±CCBwill correlate with atheroma regression as measured by IVUSwill correlate with atheroma regression as measured by IVUS

• Prospective, randomized, double-blindProspective, randomized, double-blind• Projected completion: 2002Projected completion: 2002

• Hypothesis: endothelial function improved by statin therapy ±CCBHypothesis: endothelial function improved by statin therapy ±CCBwill correlate with atheroma regression as measured by IVUSwill correlate with atheroma regression as measured by IVUS

• Prospective, randomized, double-blindProspective, randomized, double-blind• Projected completion: 2002Projected completion: 2002

Lüscher TF et al, Eur Heart J Supplements, 2000.

ENCORE II: IVUS and Endothelial FunctionENCORE II: IVUS and Endothelial FunctionENCORE II: IVUS and Endothelial FunctionENCORE II: IVUS and Endothelial Function

Limitations of IVUSLimitations of IVUSLimitations of IVUSLimitations of IVUS

• Visualizes only one artery at a timeVisualizes only one artery at a time

• Only arteries capable of accommodating theOnly arteries capable of accommodating theIVUS catheter may be examinedIVUS catheter may be examined

• May be distortedMay be distorted

• Delineates thickness and echogenicity but not Delineates thickness and echogenicity but not actual histologyactual histology

• More costly than angiography (although its benefits More costly than angiography (although its benefits may be cost-effective)may be cost-effective)

• Visualizes only one artery at a timeVisualizes only one artery at a time

• Only arteries capable of accommodating theOnly arteries capable of accommodating theIVUS catheter may be examinedIVUS catheter may be examined

• May be distortedMay be distorted

• Delineates thickness and echogenicity but not Delineates thickness and echogenicity but not actual histologyactual histology

• More costly than angiography (although its benefits More costly than angiography (although its benefits may be cost-effective)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.

Other Emerging Imaging ModalitiesOther Emerging Imaging ModalitiesOther Emerging Imaging ModalitiesOther Emerging Imaging Modalities

• AngioscopyAngioscopy uses visible light via fiberoptic filaments uses visible light via fiberoptic filaments– Allows direct examination of surface characteristics and intraluminal morphologyAllows direct examination of surface characteristics and intraluminal morphology

• DopplerDoppler uses a catheter device to measure the velocity of red blood cells and uses a catheter device to measure the velocity of red blood cells and identify flow patternsidentify flow patterns

• FFR (fractional flow reserve) FFR (fractional flow reserve) uses a nonobstructive catheter to measure flow uses a nonobstructive catheter to measure flow after maximum vasodilationafter maximum vasodilation– Compares the maximum flow of a stenotic vessel with the same vessel without Compares the maximum flow of a stenotic vessel with the same vessel without

stenosisstenosis• MRI (magnetic resonance imaging)MRI (magnetic resonance imaging) allows noninvasive imaging of the allows noninvasive imaging of the

cardiovascular systemcardiovascular system– MRI may be used to investigate coronary blood flow but the direct analysis of MRI may be used to investigate coronary blood flow but the direct analysis of

atheroma remains unlikelyatheroma remains unlikely

• AngioscopyAngioscopy uses visible light via fiberoptic filaments uses visible light via fiberoptic filaments– Allows direct examination of surface characteristics and intraluminal morphologyAllows direct examination of surface characteristics and intraluminal morphology

• DopplerDoppler uses a catheter device to measure the velocity of red blood cells and uses a catheter device to measure the velocity of red blood cells and identify flow patternsidentify flow patterns

• FFR (fractional flow reserve) FFR (fractional flow reserve) uses a nonobstructive catheter to measure flow uses a nonobstructive catheter to measure flow after maximum vasodilationafter maximum vasodilation– Compares the maximum flow of a stenotic vessel with the same vessel without Compares the maximum flow of a stenotic vessel with the same vessel without

stenosisstenosis• MRI (magnetic resonance imaging)MRI (magnetic resonance imaging) allows noninvasive imaging of the allows noninvasive imaging of the

cardiovascular systemcardiovascular system– MRI may be used to investigate coronary blood flow but the direct analysis of MRI may be used to investigate coronary blood flow but the direct analysis of

atheroma remains unlikelyatheroma remains unlikely

Nissen SE et al in Textbook of Cardiovascular Medicine, 1998; White RD in Textbook of Cardiovascular Medicine, 1998.

Diabetes: Half of All PatientsDiabetes: Half of All PatientsAre Unaware of Their ConditionAre Unaware of Their Condition

Diabetes: Half of All PatientsDiabetes: Half of All PatientsAre Unaware of Their ConditionAre Unaware of Their Condition

• CAD is the leading cause of hospitalization and death among CAD is the leading cause of hospitalization and death among patients with type 2 diabetes (NIDDM)patients with type 2 diabetes (NIDDM)

• Patients with both type 1 and type 2 diabetes are at a high short-Patients with both type 1 and type 2 diabetes are at a high short-term risk of CAD-related end pointsterm risk of CAD-related end points

• Insulin resistance increases risk and may exist for 25 years or more Insulin resistance increases risk and may exist for 25 years or more before diabetes is diagnosedbefore diabetes is diagnosed

• Patients with diabetes tend to cluster other risk factors (such as Patients with diabetes tend to cluster other risk factors (such as hypertension and dyslipidemia) while diabetes confers risk unto itselfhypertension and dyslipidemia) while diabetes confers risk unto itself

• CAD is the leading cause of hospitalization and death among CAD is the leading cause of hospitalization and death among patients with type 2 diabetes (NIDDM)patients with type 2 diabetes (NIDDM)

• Patients with both type 1 and type 2 diabetes are at a high short-Patients with both type 1 and type 2 diabetes are at a high short-term risk of CAD-related end pointsterm risk of CAD-related end points

• Insulin resistance increases risk and may exist for 25 years or more Insulin resistance increases risk and may exist for 25 years or more before diabetes is diagnosedbefore diabetes is diagnosed

• Patients with diabetes tend to cluster other risk factors (such as Patients with diabetes tend to cluster other risk factors (such as hypertension and dyslipidemia) while diabetes confers risk unto itselfhypertension 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.

UK Prospective Diabetes Study Group, BMJ, 1998.

*UK Prospective Diabetes Study Group.*UK Prospective Diabetes Study Group. *UK Prospective Diabetes Study Group.*UK Prospective Diabetes Study Group.

UKPDS*: The Case for AggressiveUKPDS*: The Case for AggressiveBlood Pressure ControlBlood Pressure Control

UKPDS*: The Case for AggressiveUKPDS*: The Case for AggressiveBlood Pressure ControlBlood Pressure Control

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

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