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
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. B-Mode Image of the
Carotid Artery Wall
plaque
plaque
5 mm
intima
carotid artery wall
media
adventitia
Courtesy of W. Riley

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. 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. 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

8. CIMT to Detect
Atherosclerosis and
CV Risk

9. 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

10. 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

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. •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

13. 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

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
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

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
25%
Control
20%
No plaque
Plaque
15%
10%
5%
0%
6 month quit rate
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 ≥.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
108 MHz: 1999
MHz: 1999

20. 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

21. 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

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
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.

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;26:1107

26. 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.

27. 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.

28. 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

29. 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

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
•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

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

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

35. 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

36. •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

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

39. 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