falk, final talk

Erling Falk: CV

SalarySalary Cardiovascular pathologistAarhus University, Denmark

Main interestMain interest Vulnerable plaquescoronary thrombosis, and

ACS

COICOI None!

Major limitationsMajor limitations

Limited insight in imaging, epidemiology, statistics prediction models, cost-effectiveness analyses etc etc

Circulation. VP Consensus Document. 2003 Oct 7;108:1664-72Circulation. VP Consensus Document. 2003 Oct 7;108:1664-72

Risk factorsRisk factors• S-chol S-chol 240 mg/dl240 mg/dl• BP >140/90BP >140/90• SmokingSmoking• DiabetesDiabetes

1 RF in >87%1 RF in >87% of CHD casesof CHD cases

JAMA 2003;290:891-7

Risk factorsRisk factors• S-chol S-chol 240 mg/dl240 mg/dl• BP >140/90BP >140/90• SmokingSmoking• DiabetesDiabetes

1 RF in >87%1 RF in >87% of CHD casesof CHD cases

JAMA 2003;290:891-7

Major risk factors account for CHD!

Nearly all adult Americans have1 risk factor, regardless of CHD

JAMA 2003;290:891-7

Predictive power of 1 risk factor for CHD

PLR <2.0:Low positive predictive power AM Weissler.

JAMA 2004;291:299-300

BMJ 1999;319:1562-5

Relative distributions of risk factors22 000 men, 10-year follow-up22 000 men, 10-year follow-up

Wald NJ, Law MR.Wald NJ, Law MR.BMJ. 2003;BMJ. 2003;

326:1419-326:1419-

~80% overlap!~80% overlap!

Serum cholesterol (mmol/l)

Diastolic blood pressure (mm/Hg)

Relative distributions of risk factors22 000 men, 10-year follow-up22 000 men, 10-year follow-up

Wald NJ, Law MR.Wald NJ, Law MR.BMJ. 2003;BMJ. 2003;

326:1419-326:1419-

~80% overlap!~80% overlap!

Serum cholesterol (mmol/l)

Diastolic blood pressure (mm/Hg)

Intermediate

Pepe et al. Am J Epidemiol 2004;159:882-90Pepe et al. Am J Epidemiol 2004;159:882-90

Eradication of Heart Attackdream or reality?dream or reality?

• Most heart attack is preventable Heart attack remains the #1 killer

Traditional approach has failed

• Most heart attack is preventable• Heart attack remains the #1 killer

Traditional approach has failed


• Most heart attack is preventable• Heart attack remains the #1 killer

Traditional approach has failedTraditional approach has failed



Vulnerable plaque (Part I)+ Vulnerable blood & myocardium (Part II, Oct 14) Vulnerable patient: high risk of near-term (Part III)



From:From: Morteza NaghaviMorteza Naghavi, M.D. [mailto:[email protected]], M.D. [mailto:[email protected]]Sent:Sent: Tue 3/1/2005 2:26 AMTue 3/1/2005 2:26 AM

… in case of symptomatic or post-ACS population we all know the balance between components of vulnerability (i.e. plaque – blood – myocardium) shifts toward increasing the role of blood and myocardium.



Diabetes and MS: Diabetes and MS: Vulnerable blood

Hypertension Hypertension && LVH: LVH: Vulnerable myocardium

Table 1. The most common polymorphisms in the hemostatic system and their associations with intermediate phenotypes and atherothrombosis disease.

Table from B Voetsch and J Loscalzo. ATVB 2004. Juan Badimon, SHAPE Report 2005

Figure 1. A schematic of the ECGI procedure.A schematic of the ECGI procedure.(a) ECG electrode vest for obtaining body surface potentials (bottom) and thoracic CT with the vest on the patient to obtain the geometries of the heart surface and the vest electrodes (top). (b) CT transverse slices showing heart contours (red) and body-surface electrodes (shiny dots). (c) Meshed heart-torso geometry. (d) Sample ECG signals obtained from mapping system. (e) Spatial representation of BSPM (body surface potentials). (f) ECGI software package (CADIS). (g) Examples of noninvasive ECGI images, including epicardial potentials, electrograms and isochrones.

Electrode vestmeasures ECG

potentials

Instrumentation setup

Transverse CT Images

Body Surfacepotentials

Heart-torsogeometry

224-channel ECG

CT provides geometry

a

b c

d e

f

g

Electrode vestmeasures ECG

potentials

Instrumentation setup

Transverse CT Images

Body Surfacepotentials

Heart-torsogeometry

224-channel ECG

CT provides geometry

a

b c

d e

f

g

Yoram Rudy, SHAPE Report 2005


Vulnerable plaque (Part I)+ Vulnerable blood & myocardium (Part II, Oct 14) Vulnerable patient: high risk of near-term Vulnerable patient: high risk of near-term (Part III)(Part III)

Lancet 2004364:937-52

Lancet 2004364:937-52

Major risk factors account for MI!but they are ”useless” for prediction!

Why?

Individual vulnerability varies greatly!Protective factors?

Lancet 2004364:937-52


Why?Why?

Individual vulnerability varies greatly!Protective factors?

Lancet 2004364:937-52


Why?Why?

Individual susceptibilitysusceptibility varies greatly!Protective factors?

Atherosclerosis and CHDrisk factors vs susceptibilityrisk factors vs susceptibility

Sir Winston Churchill, 91 Sir Winston Churchill, 91 Jim Fixx, 53Jim Fixx, 53

J RumbergerJ Rumberger

Atherosclerosis and CHDrisk factors vs susceptibilityrisk factors vs susceptibility

The 1st SHAPE Task Force Advisory Meeting, Aug 6-7, 2004, Santa MonicaSanta Monica

Photo by: Asif Ali

… just a few …

From: Morteza Naghavi, M.D. [mailto:[email protected]]Sent: Thu 2/24/2005 7:47 AMTo: Erling Falk; John Rumberger; Kaul, Sanjay M.D.; [email protected]; Kaul, Sanjay M.D.; Diamond, George, MDCc: [email protected]; Kaul, Sanjay M.D.; [email protected]; [email protected]; [email protected];

Shah, Prediman KrishanSubject: RE: Association vs classification

Let's not forget the most important question, the short-term prediction (<5y) in search of the Vulnerable Patient.

We didn't start SHAPE just to engineer a new paradigm. The concept of search for the Vulnerable Patient, those at a very high risk of a near term event is by itself a new paradigm and requires new approaches. Preventive cardiology today does not have any recognition for this group and put them all together with high risk. ……

mailto:[email protected]




Risk assessment and stratification

Risk factor/office-basedNCEP, 10-year riskIntermediate Risk

10-20%High Risk

>20%Low(er) Risk

<10%CHD CHD &&

equivalentsequivalents



10-20%High Risk

>20%Low(er) Risk

<10%

RR ~2RR ~2

CHD CHD &&equivalentsequivalents



10-20%High Risk

>20%

Susceptibility-based, near-term risk

Low(er) Risk<10%

VPVP




10-20%High Risk

>20%

Susceptibility-based, near-term risk

VPVP

Low(er) Risk<10%

Very LowRisk*

No diseaseSeverity of disease, susceptibilitysusceptibility

*Optimal risk factors


Susceptibility

VulnerableVulnerablePatientPatient

~10% risk/y~10% risk/y

Susceptibility

PROVE IT–TIMI 22



Recurrent events

Best Marker of Susceptibility to CHDprevalent arterial diseaseprevalent arterial disease

CHD risk equivalentsCHD risk equivalents

NCEP ATP III


NCEP ATP III


Susceptibility



Definition ofat-risk population

AHA’s Heart Disease and Stroke Statistics – 2004 Updatewww.americanheart.org/downloadable/heart/1079736729696HDSStats2004UpdateREV3-19-04.pdf

MW

http://www.americanheart.org/downloadable/heart/1079736729696HDSStats2004UpdateREV3-19-04.pdf




96% of deaths from CHD or stroke occur in people aged 55 and over*

*Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003;326:1419-

Circulation 2004;110:227-39Circulation 2004;110:227-39


§ Almost all people with zero or 1 risk factor have a 10-year risk <10%, § Almost all people with zero or 1 risk factor have a 10-year risk <10%, and 10-year risk assessment in people with zero or 1 risk factorand 10-year risk assessment in people with zero or 1 risk factoris thus not necessary.is thus not necessary.

Low riskLow risk• S-chol <200 mg/dlS-chol <200 mg/dl• BP BP 120/80120/80• No smokingNo smoking• No diabetesNo diabetes

JAMA 1999;282:2012-8


<10% of population<10% of population

JAMA 1999;282:2012-8


<10% of population<10% of population

High negativeHigh negativepredictive value!predictive value!

JAMA 1999;282:2012-8

Circulation Circulation 1999;100:1481-1492 1999;100:1481-1492

(no prehypertension)

(Optimal)

Circulation Circulation 1999;100:1481-1492 1999;100:1481-1492



Trajectory:How early?

Susceptibility



Risk factors:Categorical levels

Susceptibility



Vulnerability:• Relative• Absolute (VP)


Susceptibility



Vulnerability:• Relative• Absolute (VP)


Tool-dependent



Susceptibility

Vulnerability



Madjid et al. ATVB 2004;24:1775-82

ThrombusThrombus

Lipid-rich core

Vulnerable Plaque + Thrombosis + Thrombosis

Fibrouscap

Inflammation(macr, MMP)

smcsmc

Expansive growth(remodeling)

AngiogenesisAngiogenesis

Figure 1. Occurrence of a first coronary event within 10 Occurrence of a first coronary event within 10 yearsyears, estimated by Cox proportional hazards models in percentages.Left, Percentage estimated by a model with FRS (5 categories) adjusted for survey.Right, Percentage estimated for each of 5 FRS categories by a model with CRP (3 categories) adjusted for FRS (continuous) and survey. Probability values indicate significance status of CRPCRP in the Cox model.

Wolfgang Koenig, SHAPE Report 2005

Clinical utility of very high (>10 mg/L) as well as very low (<0.5 mg/L) levels of hsCRP among those with 10-year Framingham estimated risks <10% (left) and between 10% and 20% (right).

Circulation 2004;109:2818-25

CRPCRPMPOMPO

!!Pepe et al. Am J Epidemiol 2004;159:882-90Pepe et al. Am J Epidemiol 2004;159:882-90

Circulation 2004 Dec 14;110:e532

Targeted therapy,proportionate to the severity of the disease

Causal factors

Targeted therapy,proportionate to the severity of the disease

Mosca L. N Engl J Med 2002;347:1615-7. Editorial


Physical inactivity

Table 1. Direct medical costs (not charges) for numerous cardiovascular imaging and cardiac diagnostic tests as based upon the published evidence and as synthesized in the recent 34th Bethesda Conference of the American College of Cardiology and from the recent European Society for Cardiology’s Consensus Panel Report on cardiovascular magnetic resonance imaging

$39Outpatient Office Visit

$712Added Cost of Intravascular Ultrasound

$296Single Photon Emission Computed Tomography

$67Exercise ECG

$247Advanced Lipid Analysis

$13C-Reactive Protein Laboratory Measurement

$13Cholesterol panel

Comparative Costs

$1,810Right / Left Heart Cateterization

$1,272Positron Emission Tomography

$450Magnetic Resonance Imaging*

$283Other Computed Tomography

$91Rest Echocardiography

$87Electron Beam Tomography / Computed Tomography Coronary Calcium Scan

$71Carotid Ultrasound

$61Ankle Brachial Index

CV Imaging Costs

*Costs vary widely from ~$200 to $1,100 depending upon the procedure.

SHAPE: Cost-Effectiveness

Leslee Shaw, SHAPE Report 2005

Screen TestingEvaluating the Cost and Effectiveness of Strategies for Atherosclerotic Detection

and Prevention

The SHAPE EquationThe SHAPE Equation

N = nN = n0 0 f fcc f fss f fdd f ftt f fe e

N Number of prevented atherosclerotic eventsn0 Number of atherosclerotic events in the baseline populationfc Fraction of candidates in the baseline populationfs Fraction of candidates who are screenedfd Fraction of screened candidates who are detected for treatmentft Fraction of detected subjects who are effectively treatedfe Fraction of effectively treated subjects in whom events are prevented

George A. Diamond, SHAPE Writing Group

Raymond Bahr, SHAPE Report 2005

Early Heart Attack Care (EHACEHAC) andChest Pain Centers ED

Raggi et al. AHJ 2001;141:375-82Raggi et al. AHJ 2001;141:375-82

Fatal and nonfatal MIrisk and OR for each decile of calcium risk and OR for each decile of calcium

score (CS)score (CS)

Raggi et al. AHJ 2001;141:375-82Raggi et al. AHJ 2001;141:375-82

n=676, age ~52y

Author N Mean Age,

y(year

s)

Follow-up

Duration, y

(years)

Calcium Score Cutoff

ComparatorGroup for RR

Calculation

Relative Risk Ratio

Arad (11) 1,173 53 3.6 CAC>160

CAC< 160

20.2

Detrano (12) 1,196 66 3.4 CAC >44 CAC <44 2.3Park (13) 967 67 6.4 CAC

>142.1CAC <3.7 4.9

Raggi (14) 632 52 2.7 TopQuartile*

Lowest Quartile

13

Wong (15) 926 54 3.3 Top Quartile(>270)

First ScoreQuartile

8.8

Arad (16) 5,585 59 4.3 CAC ≥ 100 CAC <100 10.7Kondos (17) 5,635 51 3.1 CAC No CAC 10.5Greenland (18)

1,312 66 7.0 CAC>300 No CAC 3.9

Shaw (19) 10,377

53 5 CAC >400 CAC <10 8.4**

Pletcher (20)(meta-analysis)

3,970 56 3.3 CAC >400 CAC=0 10.0

Harvey Hecht, SHAPE Report 2005

Predictive studies: Characteristics and Risk Ratio for Follow-Up Studies Using EBCT in Asymptomatic Persons

NEJM 2003;NEJM 2003;349:465-73349:465-73

RR>10RR>10

Office-basedOffice-basedrisk assessmentrisk assessment

NEJM 1999;340:14-22

O’Leary et al. NEJM 1999;340:14-22

Figure 2: B-mode imaging of right carotid artery, bifurcation and internal and external carotid arteries. Images are obtained with ultrasound beam perpendicular to the vessel wall showing near wall, lumen and far wall. Distal 1 cm of common carotid, 1 cm of carotid bulb and 1 cm of proximal internal carotid artery are imaged for IMT measurementand detection of plaque.and detection of plaque.

Naqvi and Douglas, SHAPE Report 2005



NCEP ATP III



Future research:• Outcome studies• Disease activity• Search for the VP

From Vulnerable Plaque to Vulnerable Patient – Part III

Introducing a New Paradigm for the Prevention of Heart Attack;

Identification and Treatment of the Asymptomatic Vulnerable Patient

Screening for Heart Attack Prevention and Education (SHAPE)Task Force Report

Chairman… Editorial Committee… Writing Group … Advisors…Morteza Naghavi,…… Harvey S. Hecht, Jay Cohn, Michael Jamieson, Daniel Berman, Ole Faergeman, Matthew J. Budoff, Zahi Fayad, John Rumberger, George A. Diamond, Leslee Shaw, Tasneem Z. Naqvi, Pamela Douglas, Raymond Bahr, Wolfgang Koenig, Jasenka Demirovic, Dan Arking, Victoria L.M. Herrera, Juan Badimon, Sanjay Kaul, Juhani Airaksinen, Yoram Rudy, Arturo G. Touchard, Robert S. Schwartz, Daniel Lane, Henrik Sillesen, Roger Blumenthal, Roxana Mehran, Stephane Carlier, Allen J. Taylor, …… Prediman K. Shah.

From: From: Morteza Naghavi, M.D.Morteza Naghavi, M.D. [mailto:[email protected]]Sent: Sent: Thu 3/3/2005 1:29 AMThu 3/3/2005 1:29 AMTo: Erling FalkSubject:

Erling, please note the yellow box is Lower Risk not Low Risk, … . Mort



10-20%High Risk

>20%Low(er) Risk

<10%

RR ~2RR ~2

Pletcher et al.Arch Intern Med

2004;164:1285-92

falk, final talk

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