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