Surrogate Measures of Atherosclerosis and Implications for Evaluating Cardiovascular Risk

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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

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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

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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

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Use of Coronary Angiography in Early Studies of
Surrogate Endpoints

• The first trials of surrogate endpoints in the
  late 1980s 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

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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

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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

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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

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Carotid B-mode Ultrasonography Studies

• Atherosclerosis Risk in Communities (ARIC) (Black
  and White subjects aged 45-64) RR 5.1 in women,
  1.9 in men for IMT gt 1 mm vs. lt 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 (OLeary et al. 1999)

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Cardiovascular Health Study Combined
intimal-medial thickness predicts total MI and
stroke
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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).

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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

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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

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Interscan Variability Inversely Related to Mean
Calcium Score
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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

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Risk of Total Cardiovascular Events by Calcium
Quartile (n881)(compared to those with no
calcium age and risk-factor adjusted)Wong ND et
al., Am J Cardiol 86 295-8
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Coronary Calcium Progression
Progression of Right coronary artery calcium
score over 5 years
1993 1995 1997
Calcium Score 56 Calcium Score 90 Calcium
Score 128 Volume Score 45 Volume Score 78
Volume Score 113
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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 lt120 mg/dl, and
• moderate progression (25) in those treated less
  aggressively (LDL-C gt120 mg/dl)
• (Calister et al., NEJM 1998 339 1972-8).

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Progression of Coronary Calcium (cont)

• Other observational studies also show
  cholesterol-lowering 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)

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Flow Diagram Showing Interaction Between EBCT
Results and Clinical Management (Taylor et al.,
Western J Med 1999 171 339-41)
Click for larger picture