Transcript Surrogate Measures of Atherosclerosis and Implications in

Aortic and Carotid Magnetic
Resonance Image (MRI) Imaging
• Can identify plaque components such as fibrous cap, lipid
core, calcium, hemorrhage, and thrombosis (vunerable
plaques have thin fibrous cap and large lipid core)
• Non-invasive and no radiation
• Computerized morphometric analysis involves following
edge of significant contrast, providing measures of total
vascular and lumen area, the difference being the vessel
wall area (Image Pro-Plus, Media Cybernetics).
• Image-specific error of 2.6% for aortic and 3.5% for carotid
plaques allows accurate measurement of changes in plaque
size of >5.2% for aortic lesions and >7% for carotid lesions
(Corti et al., 2001)
MRI Assessment of Thoracic
Aorta Plaque
• Challenges include obtaining sufficient sensitivity
for sub-mm imaging and exclusion of artifacts
from respiratory motion and blood flow.
• Multicontrast approaches include performing T1,PD-, and T2-weighted images with high
resolution “black blood” spin used to visualize
adjacent vessel wall.
• Matched MRI and TEE cross-sectional aortic
images show strong correlation for plaque
composition and maximum plaque thickness.
In Vivo MRI imaging of Coronary
Artery Plaque
• Difficulties include cardiac and respiratory motion,
nonlinear course of coronary arteries, and small size
and location of coronary arteries.
• Inter- and intraobserver variability assessed by
intraclass correlation ranged from 0.96-0.99.
• Wall thickness in human coronaries can be
differentiated between normal and >40% stenosis;
breathholding can minimize respiratory motion.
• Fayad and Fuster, Am J Cardiol 2001; 88 (suppl): 42E-45E.
Lipid-Lowering by Simvastatin and
Reduction in MRI Vessel Wall Area
• 18 asymptomatic hypercholesterolemic patients
studied, with a total of 35 aortic and 25 carotid
plaques measured
• Serial black-blood MRI of aorta and carotid
artery performed at baseline, 6, and 12 months
• At 12 months (but not 6 months), significant
reductions in vessel wall thickness and area (8%
reduction in aorta and 15% reduction in carotid
artery vessel wall area), without lumen area
changes, were observed.
MRI Serial T2-Weighted Images During
Simvastatin Treatment: Coronary vessels
(top) and descending aorta (bottom)
(Corti et al., Circulation 2001; 104: 249-52)
Changes in MRI vessel wall and lumen area and wall
thickness after 6 and 12 months of simvastatin treatment
Click for
larger
picture
High-frequency Brachial
Ultrasonography
• The endothelium regulates vascular tone through
release of vasodilators and vasoconstrictors.
• Brachial artery flow-mediated vasodilation (FMD) is
assessed by high-frequency ultrasound assessment
of changes in brachial artery diameter after 5-minute
blood pressure cuff arterial occlusion.
• Endothelial dysfunction demonstrated as reduced
FMD, and associated with coronary risk factors.
• Brachial artery FMD correlates with coronary artery
FMD.
Brachial Ultrasonography (cont.)
• Brachial or coronary artery flow mediated
vasodilation (FMD) predict long-term
cardiovascular events.
• Clinical applicability not well-established, but
measures frequently used to measure endothelial
function.
• FMD decreases after age 40 in men and 50 in
women, reduced at SBP>100 mmHg, LDL > 75
mg/dl, and in diabetics
• Cholesterol reduction rapidly improves FMD.
Brachial Artery Images Pre-Post Pressure Cuff Occlusion
Click for larger picture
Intravascular Ultrasound (IVUS)
Assessment of Atherosclerosis
• Detects plaque changes resulting from
compensatory expansion that remodels the
external elastic membrane; lumen not often
narrowed until late in the process
• Invasive, expensive, normally reserved for
persons with established coronary disease
• Volume of plaque obtained by measuring
external elastic membrane, lumen area, and
plaque and repeating every mm for at least 2550 mm of artery.
IVUS: Clinical studies involving
progression/regression of plaque
• 25 patients randomized to 10 mg pravastatin vs.
placebo for 3 years showed a 41% increase in
atheroma volume in the placebo patients vs. a
7% decrease in the pravastatin patients
(p=0.0005)
• REVERSAL prospective, randomized, doubleblind multicenter trial will examine changes in
volume of plaque in patients treated with either
80 mg atorvastatin or 40 mg pravastatin;
• Nissen S, Am J Cardiol 2001; 87 (suppl): 15A-20A
Atheroma “regression” (reverse remodeling
maintaining similar lumen area) seen by IVUS
Multivariate Relative Risks of CHD/Mortality
Associated with Composite *Subclinical Disease
Men and
Women
Men Only
Women Only
Total CHD
1.99
(1.33-3.00)
1.84
(1.09-3.09)
2.41
(1.26-4.62)
Total MI
1.32
(0.75-2.32)
0.93
(0.47-1.84)
2.54
(0.87-7.43)
Total
Mortality
1.82
(1.08-3.08)
2.52
(1.18-5.37)
1.21
(0.57-2.57)
as ABI <=0.9, Internal or common carotid wall thickness >80th
%tile, carotid diameter stenosis >25%, major Minnesota ECG
abnormalities or abnormal LVEF, abnormal wall motion on
echocardiogram, or positive Rose questionnaire for claudication or
angina pectoris
* Defined
Use of Surrogate Endpoints:
Considerations in Drug Development
• Burden of sponsor is to provide evidence that the
drug is safe and effective, and often studies to
achieve clinical endpoints take longer.
• Surrogate endpoint studies can change labeling and
indications depending on results.
• But surrogate endpoints are sometimes a “leap of
faith” and an endpoint study is often still required to
validate assumptions made regarding clinical
benefit. Hard endpoint studies may not always
parallel results of surrogate endpoint studies.
LDL Cholesterol Goals and Cutpoints for
Therapeutic Lifestyle Changes (TLC)
and Drug Therapy in Different Risk Categories
Risk Category
CHD or CHD Risk
Equivalents
(10-year risk >20%)
2+ Risk Factors
(10-year risk
20%)
0–1 Risk Factor
LDL Goal
(mg/dL)
<100
<130
<160
LDL Level at Which to
Initiate Therapeutic
Lifestyle Changes
(TLC) (mg/dL)
100
130
160
LDL Level at Which
to Consider
Drug Therapy
(mg/dL)
130
(100–129: drug
optional)
10-year risk 10–
20%: 130
10-year risk <10%:
160
190
(160–189: LDLlowering drug
optional)
CHD Risk Equivalents
• Other clinical forms of atherosclerotic
disease (peripheral arterial disease,
abdominal aortic aneurysm, and
symptomatic carotid artery disease)
• Diabetes
• Multiple risk factors that confer a 10year risk for CHD >20%
LDL Cholesterol Goal and Cutpoints for
Therapeutic Lifestyle Changes (TLC) and Drug
Therapy in Patients with CHD and CHD
Risk Equivalents (10-Year Risk >20%)
LDL Goal
<100 mg/dL
LDL Level at Which
to Initiate
Therapeutic Lifestyle
Changes (TLC)
LDL Level at Which
to Consider Drug
Therapy
100 mg/dL
130 mg/dL
(100–129 mg/dL:
drug optional)
LDL-Lowering Therapy in Patients With
CHD and CHD Risk Equivalents
Baseline LDL Cholesterol: 130 mg/dL
• Intensive lifestyle therapies
• Maximal control of other risk factors
• Consider starting LDL-lowering drugs
simultaneously with lifestyle therapies
LDL-Lowering Therapy in Patients With
CHD and CHD Risk Equivalents
Baseline (or On-Treatment) LDL-C: 100–
129 mg/dL
• LDL-lowering therapy
– Initiate or intensify lifestyle therapies
– Initiate or intensify LDL-lowering drugs
• Treatment of metabolic syndrome
– Emphasize weight reduction and physical activity
• Drug therapy for other lipid risk factors
– For high triglycerides/low HDL cholesterol
– Fibrates or nicotinic acid
Implications for Cardiovascular Risk
Stratification and Treatment: NCEP III
• Should we add to this high-risk group
requiring more intensive LDL-C
initiation levels and goals, the following?
– Persons with significant carotid disease (e.g.,
at or above 5th quintile of combined IMT)
– Persons with “significant” coronary calcium
(e.g., those above 75th %tile seen to be at 46-fold or greater risk of events)
– Persons with significant LV mass or LVH
Implications on Cardiovascular Risk
Stratification and Treatment: JNC-VI
• JNC-VI currently recommends initiating drug
treatment without delay for hypertension in persons
with known CVD or diabetes at 130/85 mmHg or
higher, and in those with at least 1 risk factor when
BP is at 140/90 mmHg or higher.
• Should the presence of significant carotid disease,
CT coronary calcium, or other evidence warrant
treatment at the more aggressive, lower cut-point?
Conclusions
• Mounting data show surrogate measures of
atherosclerosis predict CHD risk and are sensitive
to monitoring effects of therapeutic interventions.
• Noninvasive methods to measure subclinical
atherosclerosis and its progression provide an
opportunity to enhance primary prevention efforts
• Noninvasive identification of the vulnerable
plaque (e.g., using MRI) may help identify those
at highest risk.
• Patient compliance to risk-reduction may be
enhanced by knowledge of disease (e.g., CAC)
Conclusions (cont.)
• Identification of those with the greatest amount of
subclinical atherosclerosis may provide a better
rationale for aggressive treatment (lipids, HTN) of those
with borderline levels, allowing us to better target
limited resources.
• Surrogate measures of atherosclerosis can also allow:
– 1) testing of epidemiologic hypotheses related to
CHD
– 2) designing clinical trials testing efficacy of
therapies
– 3) monitoring preventive therapies to reduce risk of
clinical events