Carotid IMT as a Surrogate
of Cardiovascular Disease
Risk
Allen J. Taylor MD
COL, Medical Corps
Professor of Medicine, USU...
What Is IMT ?
 IMT is the

Ultrasound Image of the Aorta in Vitro

distance
between the
lumen-intima
interface
and the me...
B-Mode Image of the
Carotid Artery Wall

plaque
plaque

5 mm

intima

carotid artery wall

media

adventitia
Courtesy of W...
What is Carotid Intima –Media Thickness
(CIMT)?
External Carotid

Normal and Diseased
Normal and Diseased
Arterial Histolo...
Portable Ultrasound for CIMT
•B mode ultrasound:
•Frequency: broadband
•Newest device 13 MHz
•Device cost: $40K +
•Specifi...
Carotid Intima-media Thickness
•Far wall
•Acoustic shadowing in
near wall
•Which site?

Selection of end-diastolic
images
...
CIMT to Detect
Atherosclerosis and
CV Risk
CIMT and Outcomes: Meta-analysis
•Meta-analysis based on random effects models
•The age- and sex-adjusted overall estimate...
The Cardiovascular Health Study
IMT and Outcomes
Relationship to CV prognosis:
•4476 pts, 65yrs+
•Risk-factor adjusted
dat...
•6698 adults aged 45 to 84 years
•23 735 person-years of follow-up
•222 incident CVD events (159 CHD events)
•59 stroke ev...
•CAC and CCA-IMT had similar hazard ratios for total
cardiovascular disease and coronary heart disease. The
CCA-IMT was mo...
An abnormal imaging study should meaningful shift
upwards a patient’s predicted CHD risk

Post-test Event
Probability (%)
...
IMT as a marker of “vascular age”
 83 patients

– Mean age 55
– ARIC data used
to adjust age

• Mean vascular
age 65

 1...
Prevention V Guidelines
Circulation 2000;101:e3-22

•Secondary prevention guidelines:
•Known CAD, and…
•CAD-equivalents: D...
Behavioral change: Potential within
factorial trials
•
•

Lausanne, Switzerland
Randomized trial in
smokers
•
•

•

N=153
...
Progression of
CIMT
Atherosclerosis: a progressive
disease
 “Typical” IMT:

– Baseline- 0.60 to 1.00 mm
– Typical progression rates ≥.01 mm/y...
Progressive Improvements in Imaging

5 MHz: 1995
108 MHz: 1999
MHz: 1999
O’
Le
ar
y
92
91
(s
ta
nd
ar
d)
Sa
lo
ne
n
91
Pe
rs
so
n
To
92
ub
Ri
ou
le
y
l9
W
92
2
en
(s
de
of
lh
tw
ag
ar
e)
97
(M
Se...
IMT Variability: Improving signal:noise
 Sources of variability for

measuring changes in
IMT progression

 Proposed sol...
Present Protocol
•13 MHz
•ECG gated, diastolic images
•Common carotid
•2 views
•2 full sets
•Analysis
•Single observer, ma...
CIMT Progression Rate: Marker of
Increased Risk for Events
Secondary Prevention, Men, Colestipol/Niacin vs
Placebo: CLAS
...
Carotid IMT…
Modestly related to cardiovascular risk
factors
and Age (a surrogate of exposure duration)
Carotid IMT- Broadly related to risk
factors

 Related to risk factors
 Relationship varies across

carotid segments
 R...
CIMT Progression: Relationship to risk
factors
age 45–64
years
n = 15,792

CIMT progression associated with:
-baseline or ...
CIMT Progression: Relationship to risk
factors
age 45–64
years
n = 15,792

DM (yes/no)

1.97 microns

Smoker

1.82 microns...
Therapeutics and IMT
•Lifestyle interventions- exercise, diet
•Lipid modifying agents•Binding resins, Niaspan, statins, CE...
RADIANCE 1 and 2:
Carotid Imaging Program
Rating Atherosclerotic Disease change by Imaging with A New CETP
inhibitor
B-mod...
Torcetrapib and CIMT

N Engl J Med 2007;356:1620-30.
Torcetrapib and CIMT

N Engl J Med 2007;356:1620-30.
Torcetrapib and CIMT: RADIANCE
2
?Net Biomarker Impact
•Systolic blood
pressure increased
by 6·6 mm Hg in the
combined-tre...
ENHANCE: Effect of Simvastatin
with or without Ezetimibe on
Carotid IMT

Simva

N Engl J Med 2008;358:1431-43

Simva + Eze...
Ezetimibe

 Licensed by the FDA in 2002 for

treatment of:
– Hypercholesterolaemia
– Homozygous sitosterolemia
ENHANCE: Effect of Simvastatin with
or without Ezetimibe on Carotid IMT
Subgroup Data
 Lipid and CIMT results

N Engl J M...
•Hard ischemic events:
NFMI, stroke, hospitalized USA, CV death
Placebo: 119/929- 12.8%
Simva/ezetimibe: 102/944- 10.8%
Ch...
SEAS:
15.6% RRR*
63% LDL
reduction

* NFMI, USA, Stroke, CV death
Limitation of CIMT
• Greater understanding of change in CIMT
progression and outcomes would be useful
• Definitive outcome...
Assessing IMT as a Biomarker
PRO

CON

•Scalable, widely used
•Noninvasive, no
incidental findings,
predicts outcomes
•Qua...
Espessamento medio intimal carótidal trials
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Espessamento medio intimal carótidal trials

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  • Slide 16. What is carotid intima–media thickness (CIMT)? [I]
    Measuring carotid intima–media thickness (CIMT) is an ultrasound technique in which the combined intima and media layer of the far wall of the carotid artery is imaged and then its mean thickness is measured using a computer program to trace the near (intima–lumen) and far (media–adventitia) wall border.
    Keywords: carotid, CIMT, IMT, ultrasound
    Slide type: figure
  • I would like to preface my remarks by indicating how important the issues of plaque burden assessment are becoming in clinical cardiology. The recent prevention conference V guidelines were published just 2 months ago in Circulation and recommend that we extend secondary prevention treatment guidelines to not only patients with established CAD, but also those who are now recognized to have CAD equivalents, that is, the presence of CAD is assumed, even in the absence of clinical CAD. These diagnoses now include diabetes mellitus, peripheral vascular disease, and plaque burden.
    Plaque burden is by a variety of means, including imaging techniques, such as EBCT, CBMU, and MRI. The authors of this AHA position paper carefully considered the available evidence for each of these tests, and felt that the data were most mature for carotid b-mode ultrasound. Specifically, wrt EBCT, they stated that:…
    As we will discuss in a few moments, this was principally based upon controversy surrounding the additive value of calcium scanning over conventional risk factor assessments for prognosis assessment.
    My job here today is to bring to you the current state of the art evidence on the use of EBCT in asymptomatic patients, and hopefully convince you that this use of EBCT is quite appropriate. Eventually, and likely in the not too distant future, the full body of evidence will be available to determine how broadly we should apply screening tests for plaque burden.
  • Slide 18. CIMT progression rate: marker of increased risk for events
    CIMT measurement is tracked across time to assess for changes in atherosclerosis extent during pharmacotherapy; slower rates of progression have been associated with lower risk from CHD in the Cholesterol Lowering Atherosclerosis Study (CLAS). In CLAS, there was a direct relationship between CIMT progression and clinical events; a 3-fold greater CIMT progression rate was associated with a 3-fold higher risk for events. These data helped establish CIMT as a valid surrogate endpoint for clinical events.
    Reference:
    Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med 1998;128:262-269.
    http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9471928
    Keywords: bile acid resins, bile acid sequestrants, carotid, CIMT, CLAS, clinical events, colestipol, combination therapy, IMT, niacin, progression, regression, ultrasound
    Slide type: figure with text
  • Lipid management is another area of impact for EBCT, where the scan results can be used to guide the intensity of lipid reduction therapies.
    This study, published in late 1998 by Tracy Callister and colleagues from Tennesse evaluated serial EBCT scans in patients, and reported the change in the calcium score according to the lipid therapy they received.
    After a mean interscan interval of approximately 1 year, the calcium scores progressed in patient with either an untreated LDL, or when the LDL remained above 120 on drug therapy. In contrast, the calcium score overall stabilized in patients when the on-treatment LDL was below 120.
    While nonrandomized, these data suggest that the most appropriate NCEP LDL target for patients with should be closer to a secondary prevention goal, representing a change in therapy for a screening population.
    An open issue is whether serial scans could be used to monitor the efficacy of therapy. Atherosclerosis regression trials have indicated that progression is associated with events, however, this use must be validated because of the inherent limitation imposed by interscan reproducibility.
  • RADIANCE 1 is a 2-year, multi-center, randomized, double-blind, parallel-group study that is being conducted at 37 recruitment and imaging centers in North America, Europe, and South Africa.1 A total of 907 men and women aged 18 to 70 years, with heterozygous FH, independent of baseline HDL-C, have been randomized. Following screening, eligible subjects commenced an atorvastatin only run-in period, during which the atorvastatin dose was titrated to a target LDL-C level according to the subject’s CV risk based on the NCEP-ATP III guidelines or to the maximally tolerated dose (20, 40, or 80 mg/day). Subjects were then randomized to either once-daily torcetrapib (60 mg) combined with atorvastatin or once-daily atorvastatin alone for 24 months. In both treatment arms, the dose of atorvastatin was that established during the run-in period. B-mode ultrasonography was performed twice within 1 week at baseline and continues every 6 months. Ultrasound will also be performed twice within 1 week prior to the last study visit. The primary efficacy measure is the annualized rate of change in maximum CIMT of 12 predefined carotid segments. Results are anticipated in early 2007.
    RADIANCE 2 is a 2-year, multi-center, randomized, double-blind, parallel-group study that is being conducted at 64 recruitment and imaging centers in North America and Europe.2 Following a 4-week washout phase when lipid-lowering therapy was discontinued, men and women aged 18 to 70 years, with mixed hyperlipidemia, independent of baseline HDL-C, commenced an atorvastatin run-in period, during which time the atorvastatin dose was titrated to a target LDL-C level as per NCEP-ATP III guidelines. Following attainment of target LDL-C levels, subjects were randomized to 24-months of treatment with either once-daily torcetrapib (60 mg) combined with atorvastatin or once-daily atorvastatin alone. In both treatment arms, the dose of atorvastatin was that established during the run-in period. B-mode ultrasonography was performed twice within 1 week at baseline and continues every 6 months. The primary efficacy measure is the annualized rate of change in maximum CIMT of 12 predefined carotid segments. A total of 758 subjects have been randomized to treatment and results should be available in early 2007.
    1. Kastelein JJP, Bots ML, Riley WA et al. Poster presentation at the 75th European Atherosclerosis Society Congress, 23-26 April 2005; Prague, Czech Republic.
    2. Bots ML, Riley WA, Evans GW et al. Poster presentation at the 75th European Atherosclerosis Society Congress, 23-26 April 2005; Prague, Czech Republic.
  • Espessamento medio intimal carótidal trials

    1. 1. 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
    2. 2. What Is IMT ?  IMT is the Ultrasound Image of the Aorta in Vitro distance between the lumen-intima interface and the mediaadventitia interface near wall  First described by Pignoli et al when imaging, with ultrasound, the wall of the abdominal Pignoli et al. Circulation. 1986;74:1399 aorta Lumen-Intima Interface Media-adventitia Interface far wall
    3. 3. B-Mode Image of the Carotid Artery Wall plaque plaque 5 mm intima carotid artery wall media adventitia Courtesy of W. Riley
    4. 4. What is Carotid Intima –Media Thickness (CIMT)? External Carotid Normal and Diseased Normal and Diseased Arterial Histology Arterial Histology Internal Carotid Internal 10 mm Bifurcation 10 mm Common Flow Divider 10 mm Skin Surface Common Carotid
    5. 5. 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
    6. 6. Carotid Intima-media Thickness •Far wall •Acoustic shadowing in near wall •Which site? Selection of end-diastolic images Systolic expansion/IMT thinning •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 Bulb Lumen Far wall IMT
    7. 7. CIMT to Detect Atherosclerosis and CV Risk
    8. 8. 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 . 2007;115:459-467
    9. 9. The Cardiovascular Health Study IMT and Outcomes Relationship to CV prognosis: •4476 pts, 65yrs+ •Risk-factor adjusted data 0 1 21.2 20.6 19.5 18.1 29 29 2 3 Quintiles of IMT O’Leary. NEJM 4 •MAXIMAL IMT •CIMT and MI/stroke: •Absolute risk exceeds 2% at 1.06 mm 5.6 10 12.8 10.4 20 16 16.1 30 12.2 Combined IMT CCA IMT ICA IMT 28 40 4.8 6.2 Incidence Rates (1000 person-years) • 5 •Risk is continuous: •RR 1.27 per 0.2 mm of CIMT increase
    10. 10. •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. 2008;168(12):1333-1339
    11. 11. •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): 186–192
    12. 12. An abnormal imaging study should meaningful shift upwards a patient’s predicted CHD risk Post-test Event Probability (%) 4% Low Middle High de I 3% tit n y Li ne 1% • 0 1% 2% 3% Focus: Intermediate risk group • CHD equivalen t 2% 0 • 4% Initial Event Probability (%) Greatest likelihood of therapeutic impact Use imaging to select for treatments guided by evidence based medicine
    13. 13. 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 40.0% 35.7% 20.0% 14.3% 0.0% Bla ck White Reclassification rates To high risk Stein et al., University of WisconsinPresented To low risk
    14. 14. Prevention V Guidelines Circulation 2000;101:e3-22 •Secondary prevention guidelines: •Known CAD, and… •CAD-equivalents: DM, ASPVD, Plaque burden •Plaque burden measurement techniques: •ABI, Carotid IMT •EBCT, MRI
    15. 15. Behavioral change: Potential within factorial trials • • Lausanne, Switzerland Randomized trial in smokers • • • N=153 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 25% Control 20% No plaque Plaque 15% 10% 5% 0% 6 month quit rate Bovet. Prev Cardiol 2002;34:215
    16. 16. Progression of CIMT
    17. 17. 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
    18. 18. Progressive Improvements in Imaging 5 MHz: 1995 108 MHz: 1999 MHz: 1999
    19. 19. O’ Le ar y 92 91 (s ta nd ar d) Sa lo ne n 91 Pe rs so n To 92 ub Ri ou le y l9 W 92 2 en (s de of lh tw ag ar e) 97 (M Se Ba an ld lze as ua r9 sa l 4 M rre et (a ho na d) Sm lo g ild sy e st 97 em (le ) ft & Ba rig ld as ht Ga ) sa rie rr e py (d 93 ig i ta ls ys (a ut W te om en m ) a t de ed lh M ag et 97 ho d) To ub ou l Absolute Differences Between Replicate Scans IMT and Progression of Atherosclerosis 0.2 0.15 0.1 0.13 0.1 Baldassarre et al. Stroke. 2000;31:1104 Stroke. 0.09 0.05 0 Reference 0.08 0.06 0.06 0.04 0.04 0.027 0.022 0.02 0.012 0.007
    20. 20. IMT Variability: Improving signal:noise  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 0.007 Readers 0.006 Subjects 0.005 0.004 0.003 0.002 0.001 0.000 Single Duplicate Single Duplicate Single Duplicate Single Duplicate 2 years Espeland et al. Stroke. 1996;27:480 Stroke. Noise 3 years 6 years 8 years
    21. 21. 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
    22. 22. CIMT Progression Rate: Marker of Increased Risk for Events Secondary Prevention, Men, Colestipol/Niacin vs Placebo: CLAS  Demonstrated value of 3  Showed that rate of common CIMT progression was directly associated with higher risk for future MI and CHD death CHD Risk changes in CIMT as an intermediate endpoint 2.8 P< 0.001 2.3 1.6 2 1 1 0 <0.011 mm/y 0.0011–0.017 mm/y 0.018–0.033 mm/y >0.033 mm/y Hodis HN et al. Ann Intern Med 1998;128:262-269.
    23. 23. Carotid IMT… Modestly related to cardiovascular risk factors and Age (a surrogate of exposure duration)
    24. 24. Carotid IMT- Broadly related to risk factors  Related to risk factors  Relationship varies across carotid segments  Relationships modest Junyent et al. ATVB 2006;26:1107
    25. 25. CIMT Progression: Relationship to risk factors age 45–64 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 2002;155:38–47.
    26. 26. CIMT Progression: Relationship to risk factors age 45–64 years n = 15,792 DM (yes/no) 1.97 microns Smoker 1.82 microns HDL (17.1 mg/dL) -.59 microns LDL (39.4 mg/dL) .22 microns Triglycerices (90 mg/dL) .43 microns Systolic BP 19 mm Hg .36 microns Am J Epidemiol 2002;155:38–47.
    27. 27. Therapeutics and IMT •Lifestyle interventions- exercise, diet •Lipid modifying agents•Binding resins, Niaspan, statins, CETPi •Anti-hypertensives •CCB’s, β blockers •Anti-diabetic agents •Metformin, TZD’s, tight diabetic control
    28. 28. RADIANCE 1 and 2: Carotid Imaging Program Rating Atherosclerotic Disease change by Imaging with A New CETP inhibitor B-mode US/6 months B-mode US S C R E E N I N G Dose titration (mg): 10 20 40 80 Atorvastatin dose titration Target: LDL-C to CV risk goal Torcetrapib/atorvastatin* R Atorvastatin* RADIANCE 1: starts at 20 mg; no wash-out period RADIANCE 2: 4 week wash-out, 4–16 week titration Study Name RADIANCE 1 RADIANCE 2 Clinical Sites PIs: J Kastelein, M Bots, W Riley Core Labs: Julius Center; Wake Forest ~25 imaging sites; 8 countries (US, CAN, FRA, ITA, NL, FIN, CZ, S.AFR) 24-month double-blind treatment *Same as atorvastatin dose at end of titration period N Primary End Point HeFH; eligible for statin treatment as per NCEP ATP III; no HDL-C criteria 907 ΔIMT (mm/year) Mixed hyperlipidemia, TG >150 mg/dL; eligible for statin treatment as per NCEP ATP III; no HDL-C criteria 758 ΔIMT (mm/year) Patient Population
    29. 29. Torcetrapib and CIMT N Engl J Med 2007;356:1620-30.
    30. 30. Torcetrapib and CIMT N Engl J Med 2007;356:1620-30.
    31. 31. Torcetrapib and CIMT: RADIANCE 2 ?Net Biomarker Impact •Systolic blood pressure increased by 6·6 mm Hg in the combined-treatment group and 1.5 mm Hg in the atorvastatinonly group (difference 5.4 mm Hg, 95% CI 4.3–6.4, p<0·0001). Lancet 2007; 370: 153–60
    32. 32. ENHANCE: Effect of Simvastatin with or without Ezetimibe on Carotid IMT Simva N Engl J Med 2008;358:1431-43 Simva + Ezetimibe
    33. 33. Ezetimibe  Licensed by the FDA in 2002 for treatment of: – Hypercholesterolaemia – Homozygous sitosterolemia
    34. 34. ENHANCE: Effect of Simvastatin with or without Ezetimibe on Carotid IMT Subgroup Data  Lipid and CIMT results N Engl J Med 2008;358:1431-43
    35. 35. •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; 359:1343
    36. 36. SEAS: 15.6% RRR* 63% LDL reduction * NFMI, USA, Stroke, CV death
    37. 37. 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 doesn’t have all the answers • Surrogates exist in potentially complementary fashion • ? BP and HDL with CETP
    38. 38. Assessing IMT as a Biomarker PRO CON •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 •Geared for groups of patients vs. individuals •Segmental response (CCA vs. ICA; IT vs. MT) may vary •Requires quality imaging protocols to ensure intertest variability is low enough to detect changes in IMT across reasonable time horizons •Trials utilizing IMT not likely to identify adverse effects

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