Carotid IMT as a Surrogate of Cardiovascular Disease Risk

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Carotid IMT as a Surrogate of Cardiovascular
Disease Risk

• Allen J. Taylor MD
• COL, Medical Corps
• Professor of Medicine, USUHS
• Chief, Cardiology Service
• Walter Reed Army Medical Center

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What Is IMT ?
Ultrasound Image of the Aorta in Vitro

• IMT is the distance between the lumen-intima
  interface and the media-adventitia interface
• First described by Pignoli et al when imaging,
  with ultrasound, the wall of the abdominal aorta

near wall
Lumen-Intima Interface
Media-adventitia Interface
far wall
Pignoli et al. Circulation. 1986741399
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B-Mode Image of theCarotid Artery Wall
Courtesy of W. Riley
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What is Carotid IntimaMedia Thickness (CIMT)?
Normal and DiseasedArterial Histology
External Carotid
Internal Carotid
10 mm
FlowDivider
Internal
10 mm
Bifurcation
10 mm
Common
SkinSurface
Common Carotid
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Portable Ultrasound for CIMT

• B mode ultrasound
• Frequency broadband
• Newest device 13 MHz
• Device cost 40K
• Specific advantages
• Clinical
• Noninvasive
• No radiation exposure
• No incidental findings
• Research
• Scalable
• Low entry costs for multicenter investigations
• Understood by clinicians

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Carotid Intima-media Thickness
Selection of end-diastolic images Systolic
expansion/IMT thinning

• Far wall
• Acoustic shadowing in near wall
• Which site?
• CCA most reproducible
• ICA/Bulb more difficult
• Plaque more common
• Greater magnitude of change
• Measurement
• ABD or manual, 1cm length
• Easy- takes minutes
• Accurate- .0x mm

Mean CIMT 1.174 mm
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CIMT to Detect Atherosclerosis and CV Risk
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CIMT and Outcomes Meta-analysis

• Meta-analysis based on random effects models
• The age- and sex-adjusted overall estimates of
  the relative risk of myocardial infarction was
  1.15 (95 CI, 1.12 to 1.17) per 0.10-mm common
  carotid artery IMT difference.
• The relationship between IMT and risk was
  nonlinear, but the linear models fitted
  relatively well for moderate to high IMT values.

Circulation. 2007115459-467
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The Cardiovascular Health StudyIMT and Outcomes

• Relationship to CV prognosis

• 4476 pts, 65yrs
• Risk-factor adjusted data
• MAXIMAL IMT
• CIMT and MI/stroke
• Absolute risk exceeds 2 at 1.06 mm
• Risk is continuous
• RR 1.27 per 0.2 mm of CIMT increase
• Pooled gender

OLeary. NEJM 199934014
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• 6698 adults aged 45 to 84 years
• 23 735 person-years of follow-up
• 222 incident CVD events (159 CHD events)
• 59 stroke events
• 50 had detectable CAC
• 1.07 mm for max internal CIMT
• 0.87 mm for max common CIMT

Arch Intern Med. 2008168(12)1333-1339
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• CAC and CCA-IMT had similar hazard ratios for
  total cardiovascular disease and coronary heart
  disease. The CCA-IMT was more strongly related to
  stroke than was CAC

Am J Cardiol. 2008 January 15 101(2) 186192
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An abnormal imaging study should meaningful shift
upwards a patients predicted CHD risk

• Focus Intermediate risk group
• Greatest likelihood of therapeutic impact
• Use imaging to select for treatments guided by
  evidence based medicine

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Identity Line
3
CHD equivalent
Post-test Event Probability ()
2
1
0
0
1
2
3
4
Initial Event Probability ()
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IMT as a marker of vascular age

• 83 patients
• Mean age 55
• ARIC data used to adjust age
• Mean vascular age 65
• 15 (1 in 7) reclassified to higher risk
• Intermediate risk patients
• 5/14 ? to high risk
• 2/14 ? to low risk

White
Black
Stein et al., University of Wisconsin- Presented
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Prevention V GuidelinesCirculation 2000101e3-22

• Secondary prevention guidelines
• Known CAD, and
• CAD-equivalents DM, ASPVD, Plaque burden
• Plaque burden measurement techniques
• ABI, Carotid IMT
• EBCT, MRI

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Behavioral change Potential within factorial
trials

• Lausanne, Switzerland
• Randomized trial in smokers
• N153
• Counseling imaging
• Smokers with plaque present and shown their
  images were 6-fold more likely to quit smoking
• Absolute 22.2 quit rate
• NNT 6

Bovet. Prev Cardiol 200234215
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Progression of CIMT
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Atherosclerosis a progressive disease

• Typical IMT
• Baseline- 0.60 to 1.00 mm
• Typical progression rates ?.01 mm/year
• Interventions affect the rate of progression of
  atherosclerosis
• This is measurable with carotid IMT
• Variability- protocol dependent
• Site
• Frequency of measurement
• Image quality
• Image interpretation
• Reader
• Methods

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Progressive Improvements in Imaging
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IMT and Progression of Atherosclerosis
Absolute Differences Between Replicate Scans
Baldassarre et al. Stroke. 2000311104
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IMT Variability Improving signalnoise
Readers
Noise
Subjects

• Sources of variability for measuring changes in
  IMT progression
• Proposed solutions
• Replicates
• Increase time interval
• Implicit solution
• Increase sample size

Variance of Measured Progression Rate
Single
Duplicate
2 years
3 years
6 years
8 years
Espeland et al. Stroke. 199627480
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Present Protocol

• 13 MHz
• ECG gated, diastolic images
• Common carotid
• 2 views
• 2 full sets
• Analysis
• Single observer, masked
• Manual and ABD
• All measurements performed twice on each image
  set
• Mean CC IMT, Max CC IMT

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CIMT Progression Rate Marker of Increased Risk
for Events
Secondary Prevention, Men, Colestipol/Niacin vs
Placebo CLAS
2.8

• Demonstrated value of changes in CIMT as an
  intermediate endpoint
• Showed that rate of common CIMT progression was
  directly associated with higher risk for future
  MI and CHD death

Plt 0.001
2.3
1.6
CHD Risk
1
lt0.011 mm/y 0.0180.033 mm/y
0.00110.017 mm/y gt0.033 mm/y
Hodis HN et al. Ann Intern Med 1998128262-269.
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Carotid IMTModestly related to cardiovascular
risk factorsand Age (a surrogate of exposure
duration)
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Carotid IMT- Broadly related to risk factors

• Related to risk factors
• Relationship varies across carotid segments
• Relationships modest

Junyent et al. ATVB 2006261107
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CIMT Progression Relationship to risk factors
age 4564 years n 15,792
CIMT progression associated with -baseline or
new diabetes -smoking -high density lipoprotein
cholesterol -pulse pressure, new HTN -change in
low density lipoprotein -change in triglycerides
Am J Epidemiol 20021553847.
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CIMT Progression Relationship to risk factors
age 4564 years n 15,792
Am J Epidemiol 20021553847.
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Therapeutics and IMT

• Lifestyle interventions- exercise, diet
• Lipid modifying agents-
• Binding resins, Niaspan, statins, CETPi
• Anti-hypertensives
• CCBs, ? blockers
• Anti-diabetic agents
• Metformin, TZDs, tight diabetic control

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RADIANCE 1 and 2 Carotid Imaging Program
Rating Atherosclerotic Disease change by Imaging
with A New CETP inhibitor
B-mode US
B-mode US/6 months
S C R E E N I N G
Torcetrapib/atorvastatin
Dose titration (mg) 10 20 40 80
Atorvastatin dose titration Target LDL-C to CV
risk goal
R
Atorvastatin
24-month double-blind treatmentSame as
atorvastatin dose at end of titration period
RADIANCE 1 starts at 20 mg no wash-out
periodRADIANCE 2 4 week wash-out, 416 week
titration
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Torcetrapib and CIMT
N Engl J Med 20073561620-30.
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Torcetrapib and CIMT
N Engl J Med 20073561620-30.
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Torcetrapib and CIMT RADIANCE 2?Net Biomarker
Impact

• Systolic blood pressure increased by 66 mm Hg in
  the combined-treatment group and 1.5 mm Hg in the
  atorvastatin-only group (difference 5.4 mm Hg,
  95 CI 4.36.4, plt00001).

Lancet 2007 370 15360
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ENHANCE Effect of Simvastatin with or without
Ezetimibe on Carotid IMT
Simva
Simva Ezetimibe
N Engl J Med 20083581431-43
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Ezetimibe

• Licensed by the FDA in 2002 for treatment of
• Hypercholesterolaemia
• Homozygous sitosterolemia

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ENHANCE Effect of Simvastatin with or without
Ezetimibe on Carotid IMT
Subgroup Data

• Lipid and CIMT results

N Engl J Med 20083581431-43
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• Hard ischemic events
• NFMI, stroke, hospitalized USA, CV death
• Placebo 119/929- 12.8
• Simva/ezetimibe 102/944- 10.8
• Chi-square P .21

N Engl J Med 2008 3591343
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SEAS 15.6 RRR 63 LDL reduction
NFMI, USA, Stroke, CV death
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Limitation of CIMT

• Greater understanding of change in CIMT
  progression and outcomes would be useful
• Definitive outcomes testing remains necessary
• Early in vivo probe to athero-biologic
  potential
• One surrogate doesnt have all the answers
• Surrogates exist in potentially complementary
  fashion
• ? BP and HDL with CETP
• Will not likely provide any data on adverse
  effects

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Assessing IMT as a Biomarker

• PRO
• Scalable, widely used
• Noninvasive, no incidental findings, predicts
  outcomes
• Quantitative relevance
• Atherosclerosis extent
• All atherosclerosis (not just a single component)
• Changes in IMT definitively linked to clinical
  outcomes
• Broad track record of success in clinical trials
• Modifiable with wide range of therapeutic
  interventions

• CON
• Geared for groups of patients vs. individuals
• Segmental response (CCA vs. ICA IT vs. MT) may
  vary
• Requires quality imaging protocols to ensure
  inter-test variability is low enough to detect
  changes in IMT across reasonable time horizons
• Trials utilizing IMT not likely to identify
  adverse effects