Signs of Subclinical Coronary Atherosclerosis Measured as

Coronary Artery Calcification Improve Risk Prediction of

Hard Events Beyond Traditional Risk Factors in an
Unselected General Population:

The Heinz Nixdorf Recall Study 5-Year Outcome Data
Raimund Erbel
1
, Stefan Mhlenkamp
1
, Susanne Moebus
1
, Axel
Schmermund
4
, Nils Lehmann
1
, Nico Dragano
3
, Andreas Stang
5
,
Dietrich Grnemeyer
2
, Rainer Seibel
2
, Hagen Klsch
1
, Martina
Brcker-Preu
1
, Klaus Mann
1
, J ohannes Siegrist
3
, Karl-Heinz
J ckel
1
, for the Heinz Nixdorf Recall Study Investigative Group
1
University Duisburg-Essen,
2
University Witten-Herdecke,
3
University Dsseldorf,
4
Cardioangiological Center Bethanien,
Frankfurt,
5
University Halle-Wittenberg, Germany
Presenter Disclosure
Information
<Raimund Erbel, MD, FACC, FESC, FAHA>
The following relationships exist related to this presentation:

Research Grant Company Imatron-GE modest level

Background
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)
Lwel H et al Dtsch rztebl 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
Background: Risk Classification
Greenland P et al Circulation 104:1863-1867, 2001
Grundy SM JACC 46: 173 5, 2005
FRS/NCEP ATP III
35 % Low Risk
40 %
Intermediate risk
25 % High Risk
Diabetes, stroke,
aortic aneurysma, PAD
Hard CVE or
all CV Events
< 10%
10-year
10 20%
10-year
> 20%
10- year
Imaging techniques
- CAC Screening
- Ultrasound - Carotis
Ankle-Brachial-Index (ABI)
Stress EKG (M 45 60 J)
hs C-reactive Protein
Life Style Change
Reassessment after 5years
INTENSIFIED THERAPY
of all risk factors
+
-
Electron-beam Computed Tomography for Non-Invasive
Imaging of Subclinical Coronary Atherosclerosis
- < 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 226:145-52, 2003
Schmermund et al . Z Kardiol 92:I/385,2003
Aim of the Study
Funded by the Heinz Nixdorf Foundation
(chairman: G Schmid)
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
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:
- 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
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
- blood pressure measurement [OMRON 705CP]
- blood samples taken for measurement of total cholesterol,
LDL-C, HDL-C (enzymatic methods),
- ATP III: low, intermediate and high risk categories
<10%, 1020%, >20% 10-year risk for hard events,
- electron beam CT (GE-Imatron, San Francisco),
- coronary artery calcification scoring (Agatston score)
for low, intermediate and high risk categories:
< 100, 100 399, 400 calcium score.
EBCT results not open to participants or physicians
Methods II: Risk Factors and CAC
Endpoint committee: C Bode, Freiburg (chairman)
K. Berger, Mnster; HR. Figulla, Jena; C. Hamm,
Bad Nauheim; P. Hanrath, Aachen ; W. Kpcke,
Mnster; Ringelstein, Mnster, C. Weimar, Essen;
A. Zeiher, Frankfurt
- Primary hypothesis: > 2.5 relative risk of 4
th
versus 1
st

quartile of coronary artery calcification
- Primary endpoint: fatal and non fatal myocardial infarction
- Pre-specified follow-up time: 5 years
- one-sided test; : 5% , : 10%
- calculation of means, relative risk with 2-sided 95%CI
and c-statistics (ROC/AUC)
Methods III: Sample Size Calculation
and Statistical Methods
0.8 % lost to follow-up
1.9 % alive, no information about AMI
n = 4487
without CAD
4370
study cohort:
4137 participants (53% females)
missing values for Framingham risk factors,
ATPIII variables and calcium scores (n=233)
Study Cohort
Median observation time: 5.03 yrs (mean: 5.12 0.26 yrs)
no primary endpoint
n=4044 (53% females)
primary endpoint
n=93 (30% females)
non-fatal MI :
n=64 (30% females)
*
coronary death:
n=29 (31% females)
*: MI-Group includes 1 subject who survived
sudden cardiac death (died 2 days later from cerebral bleeding)
Study Cohort
4137 (53% females)
n=107 non-coronary deaths
(43% females)
450/100.000 per year observed versus
300 500/100.000 predicted based on German
PROCAM / MONICA data
Primary Endpoints
Age [yrs]

Systolic BP [mmHg]

Total Cholesterol [mmol/l]

HDL-Cholesterol [mmol/l]

Smoking (active or former) [%]

Diabetes [%]


ATP III <10%
10-20%
>20%
628

14525

6.10.9

1.30.4

70.8%

16.9%


15.4%
38.5%
46.1%
598*

13819*

5.91.0

1.30.4

70.0%

8.5%*


30.0%
38.6%
31.4%
Men Women
events
n=65
no events
n=1891
648

13523

6.51.1

1.60.5

42.9%

17.9%


42.8%
28.6%
28.6%
598*

12821

6.11.0*

1.70.4

43.6%

6.0%*


71.5%
20.0%
8.5%
events
n=28
no events
n=2153
Demographics / Risk Factors
* *
*
: p < 0.05
Data = meanSD or %
ATP III Categories
0
8
12
20
E
v
e
n
t

R
a
t
e

i
n

5

Y
e
a
r
s

[
%
]

16
4
low inter-
mediate
high
All Subjects
low inter-
mediate
high
Men
Data = Event Rates (95%CI)
Women
low inter-
mediate
high
Event Rates stratified by
ATP III Categories
p=0.0003
P<0.0001
p=0.03
p=0.08
P=0.003
p=0.17
p=0.06
P=0.0007
p=0.10
51.5% 28.8% 19.7% 29.6% 38.6% 31.9% 71.2% 20.1% 8.8%
72.9% 16.8% 10.3% 85.0% 10.5% 4.5%
CAC Categories
0
8
12
20
E
v
e
n
t

R
a
t
e

i
n

5

Y
e
a
r
s

[
%
]

16
4
<100 100-399 400
Men
<100 100-399 400
Women
<100 100-399 400
All Subjects
Data = Event Rates (95%CI)
Event Rates stratified by
CAC Score Categories
p=0.0002
p<0.0001
p=0.0004
p=0.002
p<0.0001
p=0.02
p=0.48
p<0.0001
p=0.004
59.4% 23.8% 16.8%

Relative Risks (Men)
CAC Score
Categories
Crude Relative
Risk (95%CI)
Adjusted* Relative
Risk (95%CI)

0-99

1.00

1.00
100-399 2.77 (1.48-5.19) 2.53 (1.35-4.74)
400 5.31 (2.96-9.53) 4.65 (2.60-8.30)

Doubling of CAC
Scores (Log
2
(CAC+1))


1.32


(1.20-1.45)


1.30


(1.18-1.43)
Quartiles of
CAC Scores
1st (0-4.4) 1.00
2nd (4.4-55.55) 3.39 (0.94-12.24) 3.16 (0.88-11.29)
3rd (55.55-239.2) 6.39 (1.90-21.44) 5.69 (1.72-18.80)
4th (>239.2) 11.09 (3.42-35.92) 9.48 (2.97-30.22)
* adjusted for ATP III category

Relative Risks (Women)
CAC Score
Categories
Crude Relative
Risk (95%CI)
Adjusted* Relative
Risk (95%CI)
0-99 1.00 1.00
100-399 1.42 (0.42-4.81) 1.07 (0.29-3.97)
400 8.90 (3.94-20.11) 5.89 (2.46-14.08)

Doubling of CAC
Scores (log
2
(CAC+1))

1.25

(1.11-1.42)

1.20

(1.06-1.37)
Quartiles of
CAC Scores
1st (=0) 1.00
2nd + 3rd (>0-37.9) 1.12 (0.39-3.23) 0.90 (0.31-2.61)
4th (>37.9) 3.16 (1.33-7.48) 2.12 (0.81-5.55)
* adjusted for ATP III category
ROC Curve Analysis / C-Statistics
ATPIII categories
log(CAC+1)
ATPIII cat. + log(CAC+1)
All Subjects
**: p=0.0001 versus ATPIII
*: p=0.009 versus ATPIII
S
e
n
s
i
t
i
v
i
t
y

1 - Specificity
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
ATPIII
log(CAC+1)
ATPIII + log(CAC+1)
0.754 **
0.740 *
0.667
ROC Curve Analysis / C-Statistics
**: p < 0.0001 vs ATPIII
*: p = 0.004 vs ATPIII
Men
**: p = 0.18 vs ATPIII
*: p = 0.80 vs ATPIII
Women
Men Women
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
S
e
n
s
i
t
i
v
i
t
y

1 - Specificity
ATPIII
log(CAC+1)
ATPIII + log(CAC+1)
0.727 **
0.724 *
0.602
0.0 0.2 0.4 0.6 0.8 1.0
0.0
0.2
0.4
0.6
0.8
1.0
1 - Specificity
ATPIII
log(CAC+1)
ATPIII + log(CAC+1)
0.660
0.677 *
0.723 **
S
e
n
s
i
t
i
v
i
t
y

87.3% 9.3% 3.4%
Events Stratified by ATP III & CAC Categories
All Subjects
Data = Event Rates (95%CI)
62.9% 23.1% 14.1% 49.8% 27.4% 22.9%
51.5% 28.8% 19.7%
Low risk
0
8
12
20
E
v
e
n
t

R
a
t
e

i
n

5

Y
e
a
r
s

[
%
]

16
4
<100 100-399 400 <100 100-399 400
Intermediate risk High risk ATP III
CAC <100 100-399 400
0 10 20 % 10-year risk
ATPIII Score Risk Assessment
CAC Score

high risk



Intermediate
risk


low risk

Reclassification of ATP III Risk
Categories Using CAC
51.5% 28.8% 19.7%
Scheme according to Wilson PWF et al
JACC 41:1889 1906, 2003 with HNR data
62.9 %
23.1 %
14.1 %

Conclusion
Coronary Artery Calcium Score

- is a strong predictor of acute coronary events,

- improves risk prediction beyond traditional risk factors,

- may be valid more in men than in women,

- can be used for reclassification of individuals at intermediate ATP III risk,

- is not recommended in ATP III graded low risk subjects,

- may improve risk prediction in ATPIII high risk individuals
Funded by the Heinz Nixdorf Foundation
(chairman: G Schmidt)
International Advisory Board: T Meinertz, (chair),
by the German Foundation of Research, DFG.

University Clinic Essen, University Duisburg-Essen
Department of Cardiology (R Erbel, Chairman, S Mhlenkamp)
IMIBE (KH Jckel, Vicechairman, S Moebus: study coordinator)
Department of Endocrinology (K Mann)
Division of Laboratory Research (K Mann, M Brcker-Preu)
Institute of Health Economics (J Wasem)
University Dsseldorf
Institute of Medical Sociology ( J Siegrist, N Dragano)
Alfried Krupp Hospital (Th Budde)
University Witten/Herdecke - Bochum/Mlheim/R
Institute of Radiology and Microtherapy (D Grnemeyer)
Institute of Diagnostic and Interventional Radiology (R Seibel)

... 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
Risk factors alone seem not be reliable enough