cardiology update 2011 davos 14. 18. february...

Raimund Erbel

Department of Cardiology

West-German Heart Center

University Duisburg-Essen

www.wdhz.de

[email protected]

Cardiology Update 2011

Davos

14. – 18. February 2011

Improvement of Risk Prediction for Coronary Events

using Signs of Subclinical Atherosclerosis and Biomarkers

Leszek K Borysiewicz Kerstin Dudas et. al. Circulation 123:46-52, /2011

Proportion of CHD deaths

(%) within 28 days occurring

in hospital by sex, age, and

calendar year, 1991 to 2006.



Proportion of in-Hospital CHD Death

Women

Men

Mortality due to CHD in the

hospital (within 28 days) and out

of the hospital per 100 000

population 35 10 84 years of

age, 1991 to 2006.

Kerstin Dudas et. al. Circulation 123:46-52, /2011



Most Deaths of AMI occur out of the hospital

Assmann et al. Circulation 105:310-315, 2002

JAMA 385, 2001

B. PROCAM

A. Framingham

1.Step: Score based Risk – Stratification

Graham I et al EJCPR 14 (suppl 2:S1-113), 2007

detection of signs of

subclinical

atherosclerosis

> 20% /

10 years intensive therapy /

risk factor

modification

High risk =

equivalent to

post AMI

Low risk< 10% /

10 years

Intermediate

risk10 – 20% /

10 years

Greenland et al. Circulation 2000;101:111-116 Greenland et al. Circulation 2001;104:1863-1867

•NCEP / ATP III JAMA 2001;285:2486-97 # Erbel et al. Atherosclerosis 2007;197:662-72

+

-

2. Step based Risk – Categorization

advice for

healthy lifestyle

0

4

8

12

16

20

Low Intermediate High

p=0.003

Framingham Risk Score

Ob

serv

ed

5-y

r E

ven

t R

ate

[%

]

Events / # at Risk:

Relative Risk:

37 / 1303

2.46 (1.49-4.07)

29 / 498

5.04 (2.98-8.53)25 / 2165

1.0

p=0.0003

5.8 %

2.8 %1.2 %

2. Step: Risk Prediction for Coronary Events

using Framingham Risk Score in HNR study

Erbel R et. al. JACC 56:1397-406, 2010

Imaging techniques

Non imaging techniques

Stress ECG (M 45 - 60 J)

Biomarker

Prevalence of risk categories in Germany

> 20% /

10 years

intensive therapy /

risk factor

modification

High Risk

for healthy lifestyle

Low Risk< 10% /

10 years

Intermediate

Risk10 – 20% /

10 years

31% / 9%

30% / 71%

39% / 20%

Men / Women



+

Data from the Heinz Nixdorf Recall Study#

(incl. ATP III risk equivalents*)

-

3. Step: subclinical signs of atherosclerosis

used for further risk stratification

modified according to Erbel R et al HERZ 32:351-55, 2007

originally ERBEL R HERZ 21: 75-77, 1996

0% 20% 45% 50% 70% 90%

Invasive Methods

EKG

ECHOCARDIOGRAPHY

PET

CT/CTA

Non invasive Methods

OCT IVUS/ICD IRS

CORONARY ANGIOGRAPHY

SCINTIGRAPHY

Remodeling

Imaging of Coronary Subclinical AtherosclerosisD

i00

08

02

Vasomotion testing

MRT

Life time

Score

115

Score

2609

Score

49Ao

RVOT

LM

LAD

CAC

No CAC

56 year M

50 year M

51 year M

64 year F

Detection - Distribution – Quantification

Non-Invasive Imaging of Subclinical Coronary Atherosclerosisusing Computed Tomography

Non-Invasive Imaging of Subclinical Coronary Atherosclerosis using Computed Tomography

- < 20 s scan time

- 1-1.3 mSv X-ray exposure

- 100 ms acquisition time

- standardized protocols:

Agatston-Score

- 15-20 min total time

- 0.94 Kappa value for inter-

institutional variation

Imaging of coronary

artery calcification as

a specific sign of

atherosclerosis

Agatston et al. JACC 15:827-32, 1990

Hunold P et al Radiology 226:14552,2003

Schmermund et al . Z Kardiol 92:I/385,2003

0

4

8

12

16

20

0 <0-99 100-399 ≥ 400CAC Scoring

Ob

serv

ed

5-y

r E

ven

t R

ate

[%

]

Events / # at Risk:Crude Relative Risk:FRS-adjusted* RR:

24 / 1624

1.73 (0.85-3.52)

1.46 (0.71-3.00)

23 / 659

4.08 (2.00-8.33)

3.06 (1.48-6.32)

11 / 1287 1.01.0

33 / 396

9.75 (4.97-19.11)

6.25 (3.01-13.00)

p=0.13

p=0.002

p=0.0007

0.9 %1.5 %

3.5 %

8.3 %

3. Step: Improving Risk Prediction for Coronary Events

using Signs of Coronary Subclinical Atherosclerosis by CT

Erbel R et. al. JACC 56:1397-406, 2010

Greenland et al. ACCF/AHA 2007 Clinical expert consensus document JACC 115:402, 2007

Erbel et al JACC 56:1397-406, 2010

categories

Meta-analysis

HNR study

Meta-analysis

HNR study

Meta-analysis

HNR study

Meta-analysis

HNR study



Elias-Smale SE et al JACC 56:1407-14, 2010

Rotterdam Study



low intermediate high

NRI: 20.8% (p=0.0004)


using Signs of Subclinical Atherosclerosis by CT

demonstrated by the Net Reclassification Improvement NRI

Erbel R et. al. JACC 56:1397-406, 2010

Classification

according to FRS

Reclassification accounting

for CAC scores

Low Intermed. High Total

Coronary events

<10%

10-20%

>20%

Total Number

25

12

0

37

0

9

0

9

0

16

29

45

25

37

29

91

No coronary events

<10%

10-20%

>20%

Total

2140

805

0

2945

0

293

0

293

0

168

469

637

2140

1266

469

3875

NRI: 20.8% (p=0.0004)




Erbel R et. al. JACC 56:1397-406, 2010




Erbel R et. al. JACC 56:1397-406, 2010

Classification

according to

FRS 10-year event

rate

Reclassification accounting for

CAC scores

low intermed. high Total

with events

- low

- intermediate

- high

Total

7

27

0

34

0

12

0

12

0

18

29

47

7

57

29

93

without events

- low

- intermediate

- high

Total

933

1870

0

2803

0

479

0

479

0

246

508

754

933

2595

508

4036

NRI = 30.6% (p<0.0001)

Comparison to the FRS 6-20% instead of 10-20%

Detection of signs of

risk for CV events

Biomarker

Prevalence of risk categories in Germany

> 20% /

10 years

intensive therapy /

risk factor

modification

High Risk

advice for

for healthy lifestyle

Low Risk< 10% /

10 years

Intermediate

Risk10 – 20% /

10 years

31% / 9%

30% / 71%

39% / 20%

Men / Women



+

Data from the Heinz Nixdorf Recall Study#

(incl. ATP III risk equivalents*)

-


using Signs of Inflammation – a Biomarker

Ridker PM et al Circulation 103: 1813, 2001

*O‘Malley PG et al Am J Cardiol 85: 945, 2001

Lipoprotein (a)

Homocystein

Cholesterol (TC)

LDL-Cholesterol (LDLC)

TC/HDLC-Ratio

HS-CRP

Relative Risk of Future Cardiovascular Events

0 0.5 1 2 3 4 5 6 7 8

Calcium Score

Univariate Analysis for

cardiac deah, AMI,

revascularisation

9 10 11

n = 28.263n = 4.348*

*


using Biomarkers

0

4

8

12

16

20

<1.0 mg/L 1-3 mg/L >3 mg/LhsCRP Categories

Ob

serv

ed

5-y

r E

ven

t R

ate

[%

]Events / # at Risk:Crude Relative Risk:FRS-adjusted* RR:

31 / 1682

1.11 (0.65-1.90)

0.93 (0.54-1.60)

37 / 897

2.49 (1.49-4.16)

1.87 (1.09-3.21)

23 / 1387 1.01.0

p=0.0006

p=0.70

1.7 % 1.8 %

4.1 %

Möhlenkamp S et al JACC 2011 in press


using the Biomarker – hs-CRP



using the Biomarker – hs-CRP vs CAC

mg/L

hs-CRP

0 0.25 0.5 0.75 1

0

0.25

0.5

0.75

1

1-Specificity

Sen

sit

ivit

y AuROC-Curve:

FRS+hsCRP+log2(CAC+1): 0.760 (0.710-0.810)

FRS only: 0.691 (0.638-0.744)

FRS+log2(CAC+1): 0.752 (0.700-0.804)

FRS+hsCRP: 0.704 (0.652-0.757)p=0.34 p=0.0074

p=0.014 p=0.19



using the Biomarker – hs-CRP vs CAC

Classification

according to FRS

Reclassification accounting

for hsCRP scores

Low Intermed. High Total

Coronary events

<10%

10-20%

>20%

Total Number

25

9

0

34

0

14

0

14

0

14

29

43

25

37

29

91

No coronary events

<10%

10-20%

>20%

Total

2140

388

0

2528

0

579

0

579

0

299

469

768

2140

1266

469

3875

NRI: 7.8% (p=0.14)



using the Biomarker – hs-CRP

Net Reclassification Improvement

Risk Marker / Factor: NRI p-value Reference

Multiple Biomarker Score 26.7% p=0.005 (Zethelius, NEJM 2008)*(Troponin I, NT-proBNP, Cystatin C, CRP)

Multiple Biomarker Score 14.6% p=NS (Melander, JAMA 2009)*(MR-proADM, NT-proBNP)

HDL-Cholesterol (Framingham) 12.1% p<0.001 (Pencina, Stat Med 2008)

HDL-Cholesterol (SCORE-Data) 2.2% p=0.006 (Cooney, EJCPR 2009)

hsCRP (women) 5.7% p<0.0001 (Cook, Ann Int Med 2006)

hsCRP (men and women) 11.8% p<0.009 (Wilson Cirulation 2008)

hsCRP (men) 14.1% p<0.001 (Ridker, Circulation 2008)*

HbA1c (men) 3.4% p=0.06 (Simmons, Arch Int Med 2008)

HbA1c (women) - 2.2% p=0.27 (Simmons, Arch Int Med 2008)

CAC

HNR(ATP III, FRS 10-20%, 6-10%) 18.8, 21.7%, 30.6% p=0.0002 (Erbel, JACC 2010)*

Rotterdam FRS 10 – 20 % 14% p<0.01 also hard events,older

MESA FRS 6 – 20% 30% p<0.001 also soft endpoints

modified from Cooney et al. JACC 54 :1209-1227, 2009

Erbel R et al JACC 56 :1397- 406, 2010



Risk Marker / Factor: NRI p-value Reference

Multiple Biomarker Score 26.7% p=0.005 (Zethelius, NEJM 2008)*(Troponin I, NT-proBNP, Cystatin C, CRP)

Multiple Biomarker Score 14.6% p=NS (Melander, JAMA 2009)*(MR-proADM, NT-proBNP)

HDL-Cholesterol (Framingham) 12.1% p<0.001 (Pencina, Stat Med 2008)

HDL-Cholesterol (SCORE-Data) 2.2% p=0.006 (Cooney, EJCPR 2009)

Heart Rate 1.1% p=NS (Cooney, ESC 2009, Abstract)

hsCRP (women) 5.7% p<0.0001 (Cook, Ann Int Med 2006)

hsCRP (men and women) 11.8% p<0.009 (Wilson Cirulation 2008)

hsCRP (men) 14.1% p<0.001 (Ridker, Circulation 2008)*

hsCRP (total 7.8% p <0.14 (Möhlenkamp JACC 2011)

HbA1c (men) 3.4% p=0.06 (Simmons, Arch Int Med 2008)

HbA1c (women) - 2.2% p=0.27 (Simmons, Arch Int Med 2008)

CAC (ATP III, FRS 10-20%, 6-10%) 18.8, 21.7%, 30.6% p=0.0002 (Erbel JACC 2010)*



modified from Cooney et al. JACC 54 :1209-1227, 2009

Erbel R et al JACC 56 :1397- 406, 2010

I dedicate my lecture to Philip Poole-Wilson

and Helmut Drexler

Conclusion



In comparison to other signs of subclincial atherosclerosis

CAC seems to be the method of choice for improvement

of risk prediction.

And cardiology has to turn its attention to prevention,

because here the biggest target for risk improvement has to

be recognized as the majority of patient (60 to 80 %), who die from AMI,

die outside the hospital and do not reach the hospital.

Background for Improving

Risk Prediction

Acute onset of coronary syndromes still combined with

- up to 50 % rate of sudden deaths

Fox CS et al Circulation 110: 522-7, 2004

AHA: Heart Disease and Stroke Update 2009 at a glance

- 60 % of deaths outside the hospital with no improvement over

the last 10 years (MONICA/KORA)

Löwel H et al Dtsch Ärztebl 103:A616-22, 2006

- prevention at top of list of measures to reduce case fatality from CAD

Chambless et al (MONICA study) Circulation 96: 3849-59,1997

Aim of the Study

Funded by the Heinz Nixdorf Foundation (chairman: G Schmidţ)

International Advisory Board: Th Meinertz, (chair)

supported by German Foundation of Research

…coronary calcium as a sign of

subclinical coronary atherosclerosis

improves risk prediction for

cardiovascular events

in comparison to risk factors

Heinz Nixdorf Recall Study (HNR)

Risk Factors, Evaluation of Coronary Calcium and Lifestyle

Initiated in 1999 and started in 2000

Erbel et al In: Late breaking clinical trial, ACC 2009

Schmermund A et al Am Heart J 144:212-18, 2002

Stang A et al Eur J Epidemiol 20: 489-96, 2005

Dragano N et al Eur J Cardvasc Prev Rehab 14:568-74, 2007

Methods I

of the Heinz Nixdorf Recall Study

- prospective, population-based cohort study according to GEP

- random samples from resident registration offices

- 4814 men and women, aged 45 – 75 years (response: 56%)

between 12/2000 and 6/2003

- urban population with 1.5 million inhabitants in an big city area

of 8 million people

- study certified and recertified according to ISO 9001:2000

„... we are still living in a world where almost 1/3 of

the patients who die ... die suddenly before we were

even aware that these people were ill or that their

lives were in jeopardy. So it seems to me that the

most important problem we face is to find a way

of recognizing these people before they drop

dead and tell us that they were sick“

In: Coronary Heart Disease, 3rd Int. Symposium

Frankfurt, Kaltenbach M, Lichtlen P, Balcon R,

Bussmann WD (eds) Thieme, Stuttgart 1978; 83

Mason Sones in Frankfurt 1978

Detrano et al NEJM 2008

Erbel et al JACC 56:1397-406, 2010

MESA-Study:- population-based

- 6814 vs 4814 subjects

- age: 45-84 vs 45-75 years

- 6 vs 3 cities

- 4 vs 1 ethnic groups

- no CVD at entry

- follow-up: 3.5 vs 5 years

Comparison of MESA and HNR

not randomly vs randomly selected

CAC burden known

versus unknown results!!

1-s

en

sit

ivit

y

FRS alone

AuROC=0.79

(p=0.01 vs. CAC+FRS)

CAC+FRS

AuROC=0.83

CAC alone

AuROC=0.78

(p=0.06 vs. CAC+FRS)

HNR

0.681

HNR

0.741*

HNR

0.749**

ΔAuROC 0.51 vs 0.68

* p=0.46, ** p=0.003



Brown ER et al Radiology 247:669-75, 2008

Erbel et al JACC 56:1397-406, 2010

calcium score better than percentile cut-off values like 75th percentile

Budoff M et al J Am Coll Cardiol 53:345-52, 2009

HNR 0.749**

Hard EventsCombined End-points



Philip Alexander Poole-Wilson

death with 66 years March 4, 2009

Two weeks after last Update in Cardiology

In Davos

Helmut Drexler

died 6 months later

with 58 years



Stang A et al Am J Epidemiol 164:85-94, 2006

Erbel R et al Atherosclerosis 197:662-72, 2008

Schmermund A et Atherosclerosis 185:177-82, 2006

Greenland P et al Circulation 115:402-26, 2007

- Framingham Risk Score

- electron beam CT (GE-Imatron, San Francisco),

- for coronary artery calcification scoring (Agatston score)

- carotid ultrasound

for measuring intimal media thickness and plaques

- blood pressure at ankle and arm

for ankle-arm index (ABI) measurement

Methods II: for detection of

Subclinical atherosclerosis

RR für CAC und hsCRP

Erbel et al., (eingereicht)

Endotheliale Dysfunktion

Herrmann J, Lerman A Herz 2007 in press

39

Atherosklerose Pathogenese


Atherosklerose: Gefaesswand als Target


Atherosklerose Pathogenese


HeartScore Classification

Endotheliale

Dysfunktion

3.Prothrombotische Phänotyp

Änderung des Endothels

1. Gestörte Regulation des

vaskulären Tonus und

Struktur

2. Gesteigerte vaskuläre

Inflammation

Risikofaktoren der

Atherosklerose(Hypertonie, Dyslipidämia,

Diabetes. Rauchen,

Adipositas, Alter, Geschlecht

Mentaler Stress,

chronischeEntzündung)

EPCs(Zahlreduktion,

Funktionsstörung)

Entwicklung und

Progression

der Atherosklerose

4. Gestörte endogene

endotheliale Reparation

Giannotti/Landmesser Herz 32:568-72, 2007

Schmermund et al Atherosclerosis 2006

0

10

20

30

40

50

60

70

0-9 10-99 100-399 400-999 >= 1000

Männer

Frauen

% P

art

icip

ants Prevalence of

CAC

82 % Men

55 % Women

Male

Female


McClelland et al. Circulation 2006

Schmermund et al Atherosclerosis 2006

80757065605550 80757065605550

0

500

1000

1500

2000

2500

3000

MESA

Age/years

0

100

200

300

400

Ag

ats

ton

CA

C S

co

re

50th CAC-Percentile 90th CAC-Percentile

Ag

ats

ton

CA

C S

co

re

HNR

MESA multiethnic study of atherosclerosis

MESA

HNR

Age/years


46

Age/years

Jöckel et al Atherosclerosis 2008

no smoking

30 cigaretts/die, stop 20 years ago

30 cigaretts/die

Current

Smoking

Former

smoking

no-

smoking

CA

C A

gats

ton

Sco

re U

nit

smoking and coronary artery calcification


adjusted for age, sex, education, smoking, hypertension, D.m., cholesterol, living area

-100

-50

0

50

100

150

200

250

300

Distanz >200;

PM<=22 (1041)

Distanz >200;

PM>25 (84)

Rest (3339) Distanz <=100;

PM<=22 (303)

Distanz <=100;

PM>25 (38)

Verä

nd

eru

ng

des K

alk

sco

re [

%]

Ch

an

ge o

f C

AC

/ %

B Hoffmann et al Circulation116:489-496, 2007

adjusted analysis


pollution and coronary artery calcification

Co

ron

ary

art

ery

calc

ific

ati

on

Ag

ats

ton

Sco

re U

nit

WomenMen

N Dragano et al Eur J Cardiovasc Prev Rehabil 14:568-74 2007

Co

ron

ary

art

ery

calc

ific

ati

on

Ag

ats

ton

Sco

re U

nit

Income quartiles Income quartiles

socio-economics and coronary artery calcification


Folie 49 Titel

Classification

according to

FRS 10-year event

rate

Reclassification accounting for

CAC scores

low intermed. high Total

with events

- low

- intermediate

- high

Total

7

27

0

34

0

12

0

12

0

18

29

47

7

57

29

93

without events

- low

- intermediate

- high

Total

933

1870

0

2803

0

479

0

479

0

246

508

754

933

2595

508

4036

NRI = 30.6% (p<0.0001)

Comparison to the FRS 6-20% instead of 10-20%

Note: more correct down- than up classification in those with events

Net Reclassification Improvement by CAC in

Comparison to the Framingham Risk Score

cardiology update 2011 davos 14. 18. february...

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