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Surrogate Measures of
Atherosclerosis and
Implications for Evaluating
Cardiovascular Risk
Nathan D. Wong, Ph.D., F.A.C.C.
Associate Professor and Director
Heart Disease Prevention Program
University of California, Irvine
Why use surrogate measures?
• CHD events often occur with no clinical history
and often normal risk factors (e.g., total
cholesterol is a poor predictor)
• Most heart attacks result from coronary lesions
of less than 50% stenosis, often undetectable by
traditional methods (exercise test, angiogram)
• Subclinical atherosclerosis (carotid IMT, ABI,
CAC?) predicts coronary events
• Need to identify disease early enough to
intervene to prevent clinical events
Features of Using Surrogate
Measures of Atherosclerosis
• Use as intermediate endpoints rather than
waiting until hard endpoints occur
• May have implications for identifying and
tracking earlier, subclinical disease
• Compared to clinical event studies, studies of
surrogate endpoints are lower cost, require
fewer subjects, less-follow-up
• Use to follow progression of disease and effects
of medical intervention
Use of Coronary Angiography in
Early Studies of Surrogate Endpoints
• The first trials of surrogate endpoints in the
late 1980’s involved coronary angiography
• Cholesterol Lowering Atherosclerosis Study
(CLAS) used a qualitative angiographic
scoring in CABG pts studied 2 years apart.
• FATS and Lifestyle Heart Trial:
Quantitative Coronary Angiography
• Coronary angiography is expensive, may
underestimate disease, examines only
selected segments, limited to CAD patients
Primary Modalities for Measuring
Atherosclerotic Burden
• Carotid B-mode ultrasonography:
intimal medial thicknesses
• CT (EBT or multislice detectors):
coronary calcium score or volume
• Magnetic resonance imaging of carotid
plaques: vessel wall area
• Intravascular ultrasound (invasive)
• Brachial ultrasound
Other Noninvasive Measures
Associated with Cardiovascular Risk
• Ankle-Brachial Index (ABI) for assessment
of peripheral vascular disease
• Echocardiographic left ventricular mass /
hypertrophy, systolic (incl. Ejection
fraction) and diastolic function
• Pulse wave velocity / arterial compliance
for assessing large artery stiffness
Carotid B-Mode Ultrasonography
• Measurement of intimal medial thickness
• Non-invasive, inexpensive, no radiation
• Well-established as an indicator of
cardiovascular risk from epidemiologic studies
• Published clinical trials on utility of carotid IMT
as measure of progression of atherosclerosis and
effects of therapy
Carotid B-mode
Ultrasonography: Studies
• Atherosclerosis Risk in Communities
(ARIC) (Black and White subjects aged 4564): RR 5.1 in women, 1.9 in men for IMT >
1 mm vs. < 1 mm (Chambless et al, 1997).
• Cardiovascular Health Study (CHS)
(predominantly White, aged 65+): MI or
stroke rate 25% over 7 years in those at
highest quintile of combined IMT (O’Leary
et al. 1999)
Cardiovascular Health Study: Combined intimalmedial thickness predicts total MI and stroke
Carotid IMT: Clinical Trials
• ACAPS showed lovastatin therapy in those
aged 40-79 with elevated LDL-C to be
associated with regression in maximal IMT
(Furberg et al., Circ 1994; 90: 1679-87)
• KAPS showed in men 45-65 a 45% lower
rate of progression in those treated with
pravastatin (Salonen et al., Circ 1995; 92:
1758-64).
Coronary Calcium Evaluation:
EBT and Multidetector Scanners
• Non-invasive, moderate cost, convenient
• Detects location and quantity (score, mass,
volume) of coronary calcium, estimating
“burden of atherosclerosis”
• Highly sensitive for angiographic disease,
specificity variable depending on standard
• Reproducibility good (best at higher scores) but
similar in EBT vs. multidetector scanners
• Artifact “noise” greater in EBT scanners
Coronary Calcium Scanning

Coronary Artery
Scanning Protocol

Patient Preparation: None
ECG Triggered to 60-70%
of the R to R interval
3mm contiguous scans
From carina to the apex



Interscan Variability Inversely
Related to Mean Calcium Score
1.6
1.4
(sc1 - sc2)
m ean (sc1,sc2)
1.2
1
0.8
0.6
0.4
0.2
0
0
200
400
600
800
M ean (S can 1, S can 2)
1000
1200
Coronary Calcium: Risk Factors
and Prognosis
• Coronary calcium quantity and prevalence
increases with age; relation to risk factors
widely reported, by varies by study
• Persons with coronary calcium more likely
to begin healthful lifestyle behaviors
• Amount of coronary calcium associated
with greater risk of events from several
selected cohort studies
Risk of Total Cardiovascular Events by
Calcium Quartile (n=881)
(compared to those with no calcium; age and risk-factor adjusted)
Wong ND et al., Am J Cardiol; 86: 295-8
9
8
7
6
Relative Risk 5
(RR)
4
3
2
1
0
1 to 15
16 to 80
81 to 270
Total Calcium Score
271 +
Coronary Calcium Progression
Progression of Right coronary artery calcium score over 5 years
1993
Calcium Score: 56
Volume Score: 45
1995
Calcium Score: 90
Volume Score: 78
1997
Calcium Score: 128
Volume Score: 113
Coronary Calcium Progression
• Studies of serial EBT scanning show annual
progression of 22-52% per year
• Observational study of statin therapy in 149 patients
showed calcium volume over 1 year:
– 52% progression in those not treated
– regression (-7%) alcium volume among those
treated aggressively to LDL-C <120 mg/dl, and
– moderate progression (25%) in those treated less
aggressively (LDL-C >120 mg/dl)
– (Calister et al., NEJM 1998; 339: 1972-8).
Progression of Coronary Calcium (cont)
• Other observational studies also show cholesterollowering or other therapy to relate to a reduced rate
of progression (up to 50% in some cases).
• Preliminary data relating progression to events:
– 269 asymp pts observed for 2.5 years. 20 of 22
events occurred in those with progression of
calcium (Raggi, Radiology 1999; 213: 351)
– 225 asymp pts scanned avg 3 years apart ; 23 had
events and showed increase in score of 35%/yr,
compared to 22% in those without events (Shah,
Circulation 2000; 102; II: 604)
Flow Diagram Showing Interaction Between
EBCT Results and Clinical Management
(Taylor et al., Western J Med 1999; 171: 339-41)
Screening EBCT in Asymptomatic Patients
Men aged 40+ or Women aged 50+
1 or More CVD Risk Factors
Negative (no calcium)
Positive (coronary calcium)
Low risk for CVD events
Risk factor modification per existing guidelines
Enhance patient risk factor modification
(motivation and education)
with abnormal results
Age-Adjusted Calcium Score
Below 75th %tile
Above 75th %tile
Survey for all CVD risk factors
Risk factor modification per
existing guidelines
Aspirin
Optimize risk factor treatments
Aggressive lipid lowering (LDL <100 mg/dl)
Aspirin
Consider non-traditional risk factors
Click for larger picture
Score > 400
Screen for Silent Ischemia
Positive exercise perfusion study:
consider beta blockers