1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

7. 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

8. 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 > 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)

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

10. 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).

11. 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

12. 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

13. Interscan Variability Inversely Related to Mean Calcium Score

14. 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

15. 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

16. Coronary Calcium Progression Calcium Score: 56 Calcium Score: 90 Calcium Score: 128 Volume Score: 45 Volume Score: 78 Volume Score: 113 1993 1995 1997 Progression of Right coronary artery calcium score over 5 years

17. 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).

18. 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)

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