espessamento medio intimal carótidal trials

Carotid IMT as a Surrogate of

Cardiovascular Disease Risk

Allen J. Taylor MDCOL, Medical CorpsProfessor of Medicine, USUHSChief, Cardiology ServiceWalter Reed Army Medical

Center

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 aorta

Pignoli et al. Circulation. 1986;74:1399

Ultrasound Image of the Aorta in Vitro

near wall

far wall

Media-adventitia Interface

Lumen-Intima Interface

B-Mode Image of theCarotid Artery Wall

5 mm5 mmcarotid artery wall

plaque

Courtesy of W. Riley

mediamedia

adventitiaadventitia

intimaintima

plaqueplaque

What is Carotid Intima–Media Thickness (CIMT)?

Common Carotid

Internal CarotidExternal Carotid

FlowDivider

10 mm

Internal

10 mm

10 mm

Bifurcation

Common

Normal and DiseasedNormal and DiseasedArterial HistologyArterial Histology

Normal and DiseasedNormal and DiseasedArterial HistologyArterial Histology

SkinSurface

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

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

BulbLumen

Far wall IMT

Selection of end-diastolic images

Systolic expansion/IMT thinning

CIMT to Detect Atherosclerosis

and CV Risk

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.

1 2 3 4 50

10

20

30

40

4.8

12.8 1

6

21.2

29

6.2

10.4

16.1 2

0.6

29

5.6

12.2

18.1

19.5

28

Combined IMTCCA IMTICA IMT

Quintiles of IMTInci

den

ce R

ate

s (1

00

0 p

ers

on

-years

)

The Cardiovascular Health StudyIMT 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

•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

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

0

1%

2%

3%

4%

0 1% 2% 3%

Iden

tity

Iden

tity

Line

Line

Initial Event Probability (%)

4%

Post-

test

Even

tP

rob

ab

ilit

y (

%)

Low Middle High

• Focus: Intermediate risk group

• Greatest likelihood of therapeutic impact

• Use imaging to select for treatments guided by evidence based medicine

CHD equivale

nt

An abnormal imaging study should meaningful shift upwards a patient’s predicted CHD risk

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

Black

White

Stein et al., University of Wisconsin- Presented

35.7%

14.3%0.0%

20.0%

40.0%

Reclassification rates

To high risk To low risk

Prevention V GuidelinesCirculation 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

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

Progression of CIMT

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

Progressive Improvements in Imaging

5 MHz: 19958 MHz: 199910 MHz: 1999

Baldassarre et al. Baldassarre et al. StrokeStroke. 2000;31:1104. 2000;31:1104

Ab

solu

te D

iffe

ren

ces

Ab

solu

te D

iffe

ren

ces

Bet

wee

n R

epli

cate

Sca

ns

Bet

wee

n R

epli

cate

Sca

ns

0.20.2

0.150.15

0.10.1

0.050.05

00

0.130.13

0.10.1 0.090.090.080.08

0.060.06 0.060.060.040.04 0.040.04

0.0270.027 0.0220.022 0.020.02 0.0120.012 0.0070.007

ReferenceReference

Perss

on 9

2

Perss

on 9

2

Bal

dass

arre

Bal

dass

arre

(ana

log

syst

em)

(ana

log

syst

em)

Bal

dass

arre

Balda

ssar

re (d

igita

l sys

tem

)

(dig

ital s

yste

m)

Rile

y 92

Rile

y 92

O’L

eary

91

O’L

eary

91

Toub

oul

92 (s

tand

ard)

Toub

oul

92 (s

tand

ard)

Salon

en 9

1

Salon

en 9

1

Toub

oul 9

2 (s

oftw

are)

Toub

oul 9

2 (s

oftw

are)

Selze

r 94

Selze

r 94

Wen

delh

ag 9

7 (M

anua

l M

etho

d)

Wen

delh

ag 9

7 (M

anua

l M

etho

d)

Wen

delh

ag 9

7

Wen

delh

ag 9

7

(aut

omat

ed M

etho

d)

(aut

omat

ed M

etho

d)

Smild

e 97

(lef

t & ri

ght)

Smild

e 97

(lef

t & ri

ght)

Gar

iepy

93

Gar

iepy

93

IMT and Progression of Atherosclerosis

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

0.0000.000SingleSingle DuplicateDuplicate SingleSingle DuplicateDuplicate SingleSingle DuplicateDuplicate SingleSingle DuplicateDuplicate

2 years2 years 3 years3 years 6 years6 years 8 years8 years

Var

ianc

e of

Mea

sure

d P

rogr

essi

on R

ate

Var

ianc

e of

Mea

sure

d P

rogr

essi

on R

ate ReadersReaders NoiseNoise SubjectsSubjects

IMT Variability: Improving signal:noise

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

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

CH

D R

isk

1

1.6

2.3

2.8P< 0.001

<0.011 mm/y

0.018–0.033 mm/y

0.0011–0.017 mm/y

>0.033 mm/y

Carotid IMT…Modestly related to cardiovascular risk

factorsand Age (a surrogate of exposure

duration)

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

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

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

Therapeutics and IMT

•Lifestyle interventions- exercise, diet

•Lipid modifying agents-

•Binding resins, Niaspan, statins, CETPi

•Anti-hypertensives

•CCB’s, blockers

•Anti-diabetic agents

•Metformin, TZD’s, tight diabetic control

Torcetrapib/atorvastatin*Torcetrapib/atorvastatin*

Atorvastatin dose titrationAtorvastatin dose titrationTarget: LDL-C to CV risk goalTarget: LDL-C to CV risk goal

Atorvastatin*Atorvastatin*

SSCCRREEEENNIINNGG

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 periodRADIANCE 2: 4 week wash-out, 4RADIANCE 2: 4 week wash-out, 4––16 week titration16 week titration

Study Name Clinical Sites Patient Population NPrimary

End Point

RADIANCE 1PIs: 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

907ΔIMT

(mm/year)

RADIANCE 2Mixed hyperlipidemia, TG >150 mg/dL; eligible for statin treatment as per NCEP ATP III; no HDL-C criteria

758ΔIMT

(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

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

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).

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

EzetimibeEzetimibe Licensed by the FDA in 2002 for

treatment of:– Hypercholesterolaemia– Homozygous sitosterolemia

ENHANCE: Effect of Simvastatin ENHANCE: Effect of Simvastatin with or without Ezetimibe on with or without Ezetimibe on

Carotid IMTCarotid IMT

Lipid and CIMT resultsLipid and CIMT results

Subgroup DataSubgroup Data

N Engl J Med 2008;358:1431-43

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

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 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

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