Espessamento medio intimal carótidal trials

Apresentação sobre ultrassom de carotidas

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. What Is IMT ?
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
aortaPignoli et al. Circulation. 1986;74:1399
Ultrasound Image of the Aorta in Vitro
near wall
far wall
Media-adventitia Interface
Lumen-Intima Interface

3. B-Mode Image of the
Carotid Artery Wall
5 mm5 mm
carotid artery wall
plaque
Courtesy of W. Riley
mediamedia
adventitiaadventitia
intimaintima
plaqueplaque

4. What is Carotid Intima–Media Thickness
(CIMT)?
Common Carotid
Internal CarotidExternal Carotid
Flow
Divider
10
mm
Internal
10
mm
10
mm
Bifurcation
Common
Normal and DiseasedNormal and Diseased
Arterial HistologyArterial Histology
Normal and DiseasedNormal and Diseased
Arterial HistologyArterial Histology
Skin
Surface

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
•Understood by
clinicians

6. Carotid Intima-media Thickness
•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
Bulb
Lumen
Far wall IMT
Selection of end-diastolic
images
Systolic expansion/IMT
thinning

8. CIMT to Detect
Atherosclerosis and
CV Risk

9. CIMT and Outcomes: Meta-analysis
Circulation. 2007;115:459-467
•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.

10. 1 2 3 4 5
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Combined IMT
CCA IMT
ICA IMT
Quintiles of IMT
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The Cardiovascular Health Study
IMT and Outcomes
•Relationship to CV prognosis:
O’Leary. NEJM
1999:340:14
•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

11. •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

12. Am J Cardiol. 2008 January 15; 101(2): 186–192
•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

13. 0
1%
2%
3%
4%
0 1% 2% 3%
Id
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L
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Id
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Initial Event Probability (%)
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Low Middle High
•Focus:
Intermediate
risk group
•Greatest
likelihood
of
therapeutic
impact
•Use imaging
to select for
treatments
guided by
evidence
based
medicine
CHD
equivalen
t
An abnormal imaging study should meaningful shift
upwards a patient’s predicted CHD risk

14. 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
Bla
ck
White
Stein et al., University of Wisconsin-
Presented
35.7%
14.3%
0.0%
20.0%
40.0%
Reclassification rates
To high riskTo low risk

15. 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

16. 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
0%
5%
10%
15%
20%
25%
6 month quit rate
Control
No plaque
Plaque
Bovet. Prev Cardiol 2002;34:215

17. Progression of
CIMT

18. Atherosclerosis: a progressive
disease
“Typical” IMT:
–Baseline- 0.60 to 1.00 mm
–Typical progression rates ³.01 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

19. Progressive Improvements in Imaging
5 MHz: 1995
8 MHz: 199910 MHz: 1999

20. Baldassarre et al. Baldassarre et al. StrokeStroke. 2000;31:1104. 2000;31:1104
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IMT and Progression of Atherosclerosis

21. Sources of variability for Sources of variability for
measuring changes in measuring changes in
IMT progressionIMT progression
Proposed solutionsProposed solutions
–ReplicatesReplicates
–Increase time intervalIncrease time interval
Implicit solutionImplicit solution
–Increase sample sizeIncrease sample size
Espeland et al. Espeland et al. StrokeStroke. 1996;27:480. 1996;27:480
0.0070.007
0.0060.006
0.0050.005
0.0040.004
0.0030.003
0.0020.002
0.0010.001
0.0000.000
SingleSingleDuplicateDuplicateSingleSingleDuplicateDuplicateSingleSingleDuplicateDuplicateSingleSingleDuplicateDuplicate
2 years2 years 3 years3 years 6 years6 years 8 years8 years
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ReadersReaders NoiseNoiseSubjectsSubjects
IMT Variability: Improving signal:noise

22. 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

23. CIMT Progression Rate: Marker of
Increased Risk for Events
Secondary Prevention, Men, Colestipol/Niacin vs
Placebo: CLAS
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
Hodis HN et al. Ann Intern Med 1998;128:262-269.
0
1
2
3
C
H
D

R
i
s
k
1
1.6
2.3
2.8
P< 0.001
<0.011 mm/y
0.018–0.033 mm/y
0.0011–0.017 mm/y
>0.033 mm/y

24. Carotid IMT…
Modestly related to cardiovascular risk
factors
and Age (a surrogate of exposure duration)

25. Carotid IMT- Broadly related to risk
factors
Related to risk factors
Relationship varies across
carotid segments
Relationships modest
Junyent et al. ATVB 2006;26:1107Junyent et al. ATVB 2006;26:1107

26. CIMT Progression: Relationship to risk
factors
Am J Epidemiol 2002;155:38–47.
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
age 45–64
years
n = 15,792

27. CIMT Progression: Relationship to risk
factors
Am J Epidemiol 2002;155:38–47.
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

28. Therapeutics and IMT
•Lifestyle interventions- exercise, diet
•Lipid modifying agents-
•Binding resins, Niaspan, statins, CETPi
•Anti-hypertensives
•CCB’s, b blockers
•Anti-diabetic agents
•Metformin, TZD’s, tight diabetic control

29. Torcetrapib/atorvastatin*Torcetrapib/atorvastatin*
Atorvastatin dose titrationAtorvastatin dose titration
Target: LDL-C to CV risk goalTarget: LDL-C to CV risk goal
Atorvastatin*Atorvastatin*
SS
CC
RR
EE
EE
NN
II
NN
GG
B-mode USB-mode US
B-mode US/6 monthsB-mode US/6 months

24-month double-blind treatment24-month double-blind treatment
*Same as atorvastatin dose at end of titration period*Same as atorvastatin dose at end of titration period
RADIANCE 1: starts at 20 mg; no wash-out periodRADIANCE 1: starts at 20 mg; no wash-out period
RADIANCE 2: 4 week wash-out, 4RADIANCE 2: 4 week wash-out, 4––16 week titration16 week titration
Study Name Clinical Sites Patient Population N
Primary
End Point
RADIANCE 1
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)
HeFH; eligible for statin treatment as per
NCEP ATP III; no HDL-C criteria
907
ΔIMT
(mm/year)
RADIANCE 2
Mixed hyperlipidemia, TG >150 mg/dL;
eligible for statin treatment as per NCEP
ATP III; no HDL-C criteria
758
ΔIMT
(mm/year)
Dose titration (mg): 10 20 40 80Dose titration (mg): 10 20 40 80
RR
RADIANCE 1 and 2:
Carotid Imaging Program
Rating Atherosclerotic Disease change by Imaging with A New CETP
inhibitor

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

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

32. Torcetrapib and CIMT: RADIANCE
2
?Net Biomarker Impact
Lancet 2007; 370: 153–60
•Systolic blood
pressure increased
by 6·6 mm Hg in the
combined-treatment
group and 1.5 mm Hg
in the atorvastatin-
only group
(difference 5.4 mm
Hg, 95% CI 4.3–6.4,
p<0·0001).

33. ENHANCE: Effect of Simvastatin ENHANCE: Effect of Simvastatin
with or without Ezetimibe on with or without Ezetimibe on
Carotid IMTCarotid IMT
N Engl J Med 2008;358:1431-43
Simva Simva + Ezetimibe

34. EzetimibeEzetimibe
Licensed by the FDA in 2002 for
treatment of:
–Hypercholesterolaemia
–Homozygous sitosterolemia

35. ENHANCE: Effect of Simvastatin with ENHANCE: Effect of Simvastatin with
or without Ezetimibe on Carotid IMTor without Ezetimibe on Carotid IMT
Lipid and CIMT resultsLipid and CIMT results
Subgroup DataSubgroup Data
N Engl J Med 2008;358:1431-43

36. N Engl J Med 2008; 359:1343
•Hard ischemic events:
NFMI, stroke, hospitalized USA, CV death
Placebo: 119/929- 12.8%
Simva/ezetimibe: 102/944- 10.8%
Chi-square: P = .21

37. SEAS:
15.6% RRR*
63% LDL
reduction
* NFMI, USA, Stroke, CV death

38. 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
•Will not likely provide any data on adverse
effects

39. 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