Screening for Early Detection and Treatment of Asymptomatic Atherosclerotic Patients

Carotid Intima Media Thickness (CIMT)

Daniel H. O’Leary, M.D.

Presenter Disclosure Information

Disclosure Information...

The following relationships exist related to this presentation:

Daniel H. O’Leary, M.D.

- Serves as a consultant to Sanofi-Aventis and AstraZenica

- Owns stock in Medpace, Inc.

internal carotid artery common carotid artery

carotid bulb

carotid dilatation

external carotid artery carotid flowdivider

Ultrasound measurement of CIMT

probe

blood flow

CIMT

• Thin IMT in CCA

• Thicker IMT in CCA

Wall Line Interface

Near Wall

1 Adventitia - Periadventitia

2 Media - Adventitia

3 Lumen - Intima

Far Wall

4 Lumen - Intima

5 Media-Adventitia

6 Adventitia - Periadventitia

Near and Far Wall Identification

Some of the major epidemiology studies linking CIMT and incident CVD endpoints

• Chambless et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis in Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol 1997;146:483-494

• Bots et al. Common carotid intima-media thickness and risk of stroke and myocardial infarction: the Rotterdam Study. Circulation 1997;96:1432-1437

• O’Leary et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults: the Cardiovascular Health Study. N Engl J Med 1999;340:14-22

• Lorenz MW, et al. Carotid Intima-Media Thickening Indicates a Higher Vascular Risk Across a Wide Age Range: Prospective Data from the Carotid Atherosclerosis Study (CAPS) Stroke 2006;37:87

• (Pignoli P, Tremoli E, Poli A, Paoletti R. Circulation 1986; 74:1399)

Cardiovascular Health Study: Baseline CIMT Predictive of CHD

• 4,476 subject without CHD at baseline• Median follow-up 6.2 yrs• RR of stroke/MI for highest vs. lowest CIMT quintile was 3.87

0 1 2 3 4 5 6 7

1st Quintile

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2nd Quintile

3rd Quintile

4th Quintile

5th Quintile

O’Leary et al, N Engl J Med. 1999;340:14-22

Summation of the major studies assessing the value of CIMT in assessing individual risk

• Meta-analysis involving eight relevant studies representing 37259 subjects

• Age- and sex-adjusted relative risk of MI was 1.26 per one SD CCA-IMT difference and 1.15 per 0.10mm CCA-IMT difference

• Age- and sex-adjusted relative risk of stroke was 1.32 per one SD CCA-IMT difference and 1.18 per 0.10mm CCA-IMT difference

Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events using carotid intima-media thickness: a systematic review and meta-analysis. Circulation 2007;106:459-467

Hazard ratios for incident CVD event in relation to quartiles of CIMT or CAC in MESA

• Measure HR

• <50th percentile 3rd quartile 4th quartile• age, race, sex-adjusted

• CIMT 1.0 1.4 2.2

• CAC score 1.0 2.6 5.3

Folsom AR, Kronmal RA, Detrano RC, O’Leary DH, et al. Coronary artery calcium compared with carotid intima-media thickness in prediction of cardiovascular disease incidence: the Multi-Ethnic Study of Atherosclerosis (MESA). Arch Intern Med 2008;168:1333-1339

CVD events by coronary artery calcium and internal carotid wall thickness quartiles in CHS

Newman AB, Naydeck BL, Ives DG, Boudreau RM, Sutton-Tyrrell K, O’Leary DH, Kuller LH. Coronary artery calcium, carotid artery wall thickness, and CVD outcomes in adults 70 to 90 years old. Am J Cardiol 2008; 101:186-192

At 4.5 yrs, % remaining alive are:

87%84%78%72%

At 4.5 yrs, % remaining alive are:

85%82%79%75%

IMT Definition of Plaque

• a focal structure that encroaches into the arterial lumen of at least 0.5 mm or 50% of the surrounding IMT value

or• a thickness > 1.5 mm as measured from the media-

adventia interface to the intima-lumen interface

Mannheim Carotid Intima-Media Thickness Consensus (2004-2006). Cerebrovasc Dis 2007;23:75-80

Ultrasound Reading Center for the following NIH-sponsored studies

• CHS (Cardiovascular Health Study)> 5000 X 3 visits (1989, 1993, 1997)

• IRAS (Insulin Resistance in Atherosclerosis) 1625 in 1992, 1192 in 1997

• EDIC (Epidemiology of Diabetes Interventions and Complications

1375 in 1994, 1229 in 1998, 1189 in 2006

• Framingham Heart Study Offspring cohort

3252 in 1995-98, 3100 in 2005-07

• MESA (Multi-Ethnic Study of Atherosclerosis)

>6200 in 2000, ½ in 2002, ½ in 2004, ¼ in 2006

• CARDIA (Cardiovascular Risk Development in young Adults)3244 in 2004

Several informed generalizations

1. Plaque characterization is of no value in managing individual patients

2. Sequential ultrasound examinations are of no value in assessing therapeutic response in individuals

3. TPA (Total Plaque Area) measurements are of unclear value to me – need large prospective multicenter studies linked to outcomes

Are there subsets of the population where the value added by bio-imaging could be shown to be cost-

effective?

• Goal is to identify and treat persons at high risk for CVD• Treating major CVD risk factors for 1° and 2° prevention works

and guidelines support this• Framingham risk scores that predict a 10-20% risk of CHD over

10 years are considered at “intermediate risk”, and those with greater risk, at “high risk”

• Minority of persons who develop CVD are at “high risk”• There are 23 million in US population at intermediate risk, having

approximately 30,000 CVD events annually• There is a paucity of information on effectiveness of screening

and treating asymptomatic CHD

Recommendations for screening

• AHA Prevention V (Greenland et al., Circ. 2000) persons at intermediate risk may be suitable for screening by noninvasive tests, including ABI and carotid US, for those over age 50 years

• Task force 4, 34th Bethesda Conference (Wilson et al., JACC 2003; 41: 1898-1905) patients at intermediate risk for total CHD event possibly warrant further risk stratification by noninvasive tests to assess atherosclerotic burden

• ACCF/AHA 2007 clinical expert consensus document on coronary artery scoring by CT on global risk assessment (Greenland et al. J Am Coll Cardiol 2007) stated it reasonable to obtain CAC in asymptomatic patients with intermediate CHD risk, based on possibility of reclassification to a higher risk status and altered medical management

Consensus statement from the American Society of Echocardiography CIMT Task Force

• CIMT measurements of far wall CCA only• Scan extracranial carotid arteries (CCA, bulb, ICA) for

presence of focal plaque• Presence of plaque or far wall CCA CIMT greater or equal

to the 75th percentile for the patient’s age, sex, and race/ethnicity are indicative of increased CVD risk and may signify the need for more aggressive risk reductions

• Serial studies of CIMT to address progression or regression are not recommended

Stein JH et al. J American Society of Echocardiography 2008;21:93-111

Subclinical Disease Testing and Risk of Disease

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Initial Probability (%)Slide courtesy N Wong (modified by DOL)

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Positive test stratifies risk upward

Negative test does not stratify risk downward

The First SHAPE (Screening for Heart Attack Prevention and Education) Guideline

• Goal to address major shortcoming in existing guidelines in primary prevention of CVD

• Most heart attacks and strokes occur in people not classified as high risk and thus not aggressively treated

• Concept that “vulnerable patient” can be identified by bio-imaging rather than screening for risk factors

• Recommends non-invasive screening of all asymptomatic men 45-75 yrs and asymptomatic women 55-75 yrs (except those defined as very low risk) using either CT or ultrasound as initial test

Naghavi et al. Am J Cardiol 2006;98:2H-15H

How early in life should we be treating individuals to lessen their risk of CVD?

• “Let the cholesterol fight begin , at age 8” – headline in USA TODAY, July 8, 2008

• “Strongest guidance ever given on the issue by the American Academy of Pediatrics”

• “The new advice is based on mounting evidence showing that damage leading to heart disease begins early in life, as well as research showing that cholesterol-fighting drugs are generally safe for children”

• CIMT correlates better with previously measured risk factors than with those measured concurrently

What do the payers say?

• Most payers have declared CIMT experimental and not medically indicated

• Medicare: Category III CPT code 0126T• Category III codes apply to new technologies and

are not reimbursed by many payers• Usual rationale is that there are no convincing

studies linking CIMT measurement to improved clinical outcomes

In conclusion, I

• Would not screen patients >65 years of age• Would not screen patients at either high risk or low risk• Would not rank Atherosclerosis Test as Step 1• Would wait at least 5 years before considering repeat AT• Would ask – how many subjects will be reclassified

because of AT? How many new patients will be treated, what will be the impact on outcomes, and at what cost?

• Would focus on early life intervention for a disease that is present decades prior to diagnosis by any imaging test