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
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)
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
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 RiskDiabetes, stroke,aortic aneurysma, PAD
Hard CVE orall 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 ChangeReassessment 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 coronaryartery 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 )ţInternational 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, 2002Stang A et al Eur J Epidemiol 20: 489-96, 2005Dragano 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, 2006Erbel R et al Atherosclerosis 197:662-72, 2008Schmermund A et Atherosclerosis 185:177-82, 2006Greenland 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%, 10–20%, >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, Münster; HR. Figulla, Jena; C. Hamm, Bad Nauheim; P. Hanrath, Aachen ; W. Köpcke, Münster; Ringelstein, Münster, C. Weimar, Essen; A. Zeiher, Frankfurt
- Primary hypothesis: > 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; α: 5% , β: 10%
- calculation of means, relative risk with 2-sided 95%CI and c-statistics (ROC/AUC)
Methods III: Sample Size Calculationand Statistical Methods
0.8 % lost to follow-up
1.9 % alive, no information about AMI
n = 4487without 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 Cohort4137 (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%
62±8
145±25
6.1±0.9
1.3±0.4
70.8%
16.9%
15.4%38.5%46.1%
59±8*
138±19*
5.9±1.0
1.3±0.4
70.0%
8.5%*
30.0%38.6%31.4%
Men Womenevents n=65
no eventsn=1891
64±8
135±23
6.5±1.1
1.6±0.5
42.9%
17.9%
42.8%28.6%28.6%
59±8*
128±21
6.1±1.0*
1.7±0.4
43.6%
6.0%*
71.5%20.0%8.5%
eventsn=28
no eventsn=2153
Demographics / Risk Factors
* *
* : p < 0.05
Data = mean±SD or %
ATP III Categories
0
8
12
20
Eve
nt
Rat
e in
5 Y
ears
[%
]
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
Eve
nt
Rat
e in
5 Y
ears
[%
]
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 ScoreCategories
Crude Relative Risk (95%CI)
Adjusted* Relative Risk (95%CI)
0-99
1.00 1.00100-399 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 CACScores (Log2(CAC+1))
1.32 (1.20-1.45) 1.30 (1.18-1.43)
Quartiles of CAC Scores 1st (0-4.4) 1.002nd (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 1.00100-399 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(CAC+1))
1.25 (1.11-1.42) 1.20 (1.06-1.37)
Quartiles of CAC Scores 1st (=0) 1.002nd + 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
Sen
sitiv
ity
1 - Specificity0.0 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
Sen
sitiv
ity
1 - Specificity
ATPIIIlog(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
ATPIIIlog(CAC+1)ATPIII + log(CAC+1)
0.660
0.677 *
0.723 **
Sen
sitiv
ity
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
Eve
nt
Rat
e in
5 Y
ears
[%
]
16
4
<100 100-399 ≥400 <100 100-399 ≥400
Intermediate risk High riskATP III
CAC <100 100-399 ≥400
0 10 20 % 10-year riskATPIII Score Risk Assessment
CAC Score
high risk
Intermediaterisk
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 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)
„... 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