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:

1
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 Möhlenkamp 1, Susanne
Moebus 1, Axel Schmermund 4, Nils Lehmann 1,
Nico Dragano 3, Andreas Stang 5, Dietrich
Grönemeyer 2, Rainer Seibel 2, Hagen Kälsch 1,
Martina Bröcker-Preuß 1, Klaus Mann 1, Johannes
Siegrist 3, Karl-Heinz Jöckel 1, for the Heinz
Nixdorf Recall Study Investigative Group
1University Duisburg-Essen, 2 University
Witten-Herdecke, 3 University Düsseldorf, 4
Cardioangiological Center Bethanien, Frankfurt,
5 University Halle-Wittenberg, Germany
2
Presenter Disclosure Information
ltRaimund Erbel, MD, FACC, FESC, FAHAgt
The following relationships exist related to this
presentation
Research Grant Company Imatron-GE
modest level
3
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)
• Löwel H et al Dtsch Ärztebl
  103A616-22, 2006
• prevention at top of list of measures to reduce
  case fatality from CAD
• Chambless et al (MONICA study)
  Circulation 96 3849-59,1997

4
Background Risk Classification
Hard CVE or all CV Events
Life Style Change Reassessment after 5years
FRS/NCEP ATP III
-
lt 10 10-year
35 Low Risk

• ? Imaging techniques
• - CAC Screening
• - Ultrasound - Carotis
• ? Ankle-Brachial-Index (ABI)
• Stress EKG (M 45 60 J)
• hs C-reactive Protein

40 Intermediate risk
10 20 10-year
25 High Risk Diabetes, stroke, aortic
aneurysma, PAD
gt 20 10- year

INTENSIFIED THERAPY of all risk factors
Greenland P et al Circulation
1041863-1867, 2001 Grundy SM
JACC 46 173 5, 2005
5
Electron-beam Computed Tomography for
Non-Invasive Imaging of Subclinical Coronary
Atherosclerosis
- lt 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 15827-32, 1990
Hunold P et al
Radiology 226145-52, 2003
Schmermund et al . Z Kardiol 92I/385,2003
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Aim of the Study
Heinz Nixdorf Recall Study
(HNR) Risk Factors, Evaluation of Coronary
Calcium and Lifestyle
coronary calcium as a sign of subclinical
coronary atherosclerosis improves risk
prediction for cardiovascular events in
comparison to risk factors
Initiated in 1999 and started in 2000
Funded by the Heinz Nixdorf Foundation
(chairman G
Schmidt) International Advisory Board Th
Meinertz, (chair) supported by German
Foundation of Research
7
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 90012000

Schmermund A et al Am Heart J 144212-18,
2002 Stang A et al Eur J Epidemiol 20
489-96, 2005 Dragano N et al Eur J Cardvasc Prev
Rehab
14568-74, 2007


8
Methods II Risk Factors and CAC

• - 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
• lt10, 1020, gt20 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
• lt 100, 100 399, 400 calcium score.
• EBCT results not open to participants or
  physicians

Stang A et al Am J Epidemiol 16485-94,
2006 Erbel R et al Atherosclerosis
197662-72, 2008 Schmermund A et
Atherosclerosis 185177-82, 2006 Greenland P et
al Circulation 115402-26, 2007
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Methods III Sample Size Calculation and
Statistical Methods

• - Primary hypothesis gt 2.5 relative risk of 4th
  versus 1st
  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 95CI
• and c-statistics (ROC/AUC)

Endpoint committee C Bode, Freiburg
(chairman) K. Berger, Münster HR. Figulla, Jena
C. Hamm, Bad Nauheim P. Hanrath, Aachen W.
Köpcke, Münster Ringelstein, Münster, C.
Weimar, Essen A. Zeiher, Frankfurt
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Study Cohort
n 4487 without CAD
0.8 lost to follow-up
1.9 alive, no information about AMI
4370
missing values for Framingham risk factors,
ATPIII variables and calcium scores (n233)
study cohort 4137 participants (53 females)
Median observation time 5.03 yrs (mean 5.12
0.26 yrs)
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Primary Endpoints
Study Cohort 4137 (53 females)
non-fatal MI n64 (30 females)
primary endpoint n93 (30 females)
coronary death n29 (31 females)
no primary endpoint n4044 (53 females)
n107 non-coronary deaths (43 females)
MI-Group includes 1 subject who survived
sudden cardiac death (died 2 days later from
cerebral bleeding)
450/100.000 per year observed versus
300 500/100.000 predicted based on German
PROCAM / MONICA
data
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Demographics / Risk Factors
Men
Women
events n65
no events n1891
events n28
no events n2153
Age yrs Systolic BP mmHg Total Cholesterol
mmol/l HDL-Cholesterol mmol/l Smoking
(active or former) Diabetes ATP III
lt10 10-20 gt20
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 3
0.0 38.6 31.4
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 7
1.5 20.0 8.5


p lt 0.05

Data meanSD or
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Event Rates stratified by ATP III Categories
ATP III Categories
Data Event Rates (95CI)
14
Event Rates stratified by CAC Score Categories
CAC Categories
Data Event Rates (95CI)
15

• Relative Risks (Men)

CAC Score Categories Crude Relative Risk (95CI) Crude Relative Risk (95CI) Adjusted Relative Risk (95CI) Adjusted Relative Risk (95CI)
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 (Log2(CAC1)) 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 (gt239.2) 11.09 (3.42-35.92) 9.48 (2.97-30.22)
adjusted for ATP III category
16

• Relative Risks (Women)

CAC Score Categories Crude Relative Risk (95CI) Crude Relative Risk (95CI) Adjusted Relative Risk (95CI) Adjusted Relative Risk (95CI)
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 (log2(CAC1)) 1.25 (1.11-1.42) 1.20 (1.06-1.37)

Quartiles of CAC Scores
1st (0) 1.00
2nd 3rd (gt0-37.9) 1.12 (0.39-3.23) 0.90 (0.31-2.61)
4th (gt37.9) 3.16 (1.33-7.48) 2.12 (0.81-5.55)
adjusted for ATP III category
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ROC Curve Analysis / C-Statistics
1.0
All Subjects
0.8
0.754
0.667
0.6
ATPIII categories
Sensitivity
0.740
log(CAC1)
0.4
ATPIII cat. log(CAC1)
ATPIII
0.2
log(CAC1)
p0.0001 versus ATPIII
ATPIII log(CAC1)
p0.009 versus ATPIII
0.0
0.0
0.2
0.4
0.6
0.8
1.0
1 - Specificity
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ROC Curve Analysis / C-Statistics
Men
Women
Men
Women
p lt 0.0001 vs ATPIII
p 0.18 vs ATPIII
p 0.004 vs ATPIII
p 0.80 vs ATPIII
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Events Stratified by ATP III CAC Categories
All Subjects
CAC
Low risk
Intermediate risk
High risk
ATP III
Data Event Rates (95CI)
20
Reclassification of ATP III Risk Categories
Using CAC
CAC Score high risk Intermediate risk
low risk
23.1
0 10 20
10-year risk ATPIII Score Risk Assessment
Scheme according to Wilson PWF et al JACC
411889 1906, 2003 with HNR data
21

• 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

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• University Clinic Essen, University
  Duisburg-Essen
• Department of Cardiology (R Erbel, Chairman, S
  Möhlenkamp)
• IMIBE (KH Jöckel, Vicechairman, S Moebus study
  coordinator)
• Department of Endocrinology (K Mann)
• Division of Laboratory Research (K Mann, M
  Bröcker-Preuß)
• Institute of Health Economics (J Wasem)
• University Düsseldorf
• Institute of Medical Sociology ( J Siegrist, N
  Dragano)
• Alfried Krupp Hospital (Th Budde)
• University Witten/Herdecke - Bochum/Mülheim/R
• Institute of Radiology and Microtherapy (D
  Grönemeyer)
• Institute of Diagnostic and Interventional
  Radiology (R Seibel)

Funded by the Heinz Nixdorf Foundation
(chairman
G Schmidt) International Advisory Board T
Meinertz, (chair), by the German
Foundation of Research, DFG.
23
Mason Sones in Frankfurt 1978
... 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
Risk factors alone seem not be reliable enough

In Coronary Heart Disease, 3rd Int.
Symposium
Frankfurt, Kaltenbach M,
Lichtlen P, Balcon R,
Bussmann
WD (eds) Thieme, Stuttgart 1978 83