Power - Society for Heart Attack Prevention and Eradication

Report
Shape 2012
November 2, 2012
Lessons learned from the Heinz Nixdorf Recall study
Raimund Erbel for the Ivestigator Group
of the Heinz Nixdorf Recall study
Department of Cardiology
West-German Heart Center
University Duisburg-Essen
www.recall-studie.uni-essen.de
[email protected]
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis and Biomarkers
Proportion of in-Hospital CHD Death
Proportion of CHD deaths
(%) within 28 days occurring
in hospital by sex, age, and
calendar year, 1991 to 2006.
Women
Men
Kerstin Dudas et. al.
Leszek K Borysiewicz
Circulation 123:46-52, /2011
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis and Biomarkers
Most Deaths of AMI occur out of the hospital
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
1. Step: Score based Risk – Stratification
A. Framingham
B. PROCAM
Assmann et al. Circulation 105:310-315, 2002
JAMA 385, 2001
Graham I et al EJCPR 14 (suppl 2:S1-113), 2007
2. Step based Risk – Categorization
Low risk
< 10% /
10 years
advice for
healthy lifestyle
-
Intermediate
risk
10 – 20% /
10 years
High risk =
equivalent to
post AMI
Greenland et al.
•NCEP / ATP III
Circulation
JAMA
2000;101:111-116
2001;285:2486-97
detection of signs of
subclinical
atherosclerosis
+
> 20% /
10 years
Greenland et al.
# Erbel et al.
intensive therapy /
risk factor
modification
Circulation 2001;104:1863-1867
Atherosclerosis 2007;197:662-72
2. Step: Risk Prediction for Coronary Events
using Framingham Risk Score in HNR study
Events / # at Risk:
Observed 5-yr Event Rate [%]
Relative Risk:
20
29 / 498
5.04 (2.98-8.53)
p=0.003
16
p=0.0003
12
8
5.8 %
4
1.2 %
2.8 %
0
Low
Erbel R et. al.
37 / 1303
2.46 (1.49-4.07)
25 / 2165
1.0
Intermediate
High
Framingham Risk Score
JACC 56:1397-406, 2010
3. Step: subclinical signs of atherosclerosis
used for further risk stratification
Prevalence of risk categories in Germany
Men / Women
Low Risk
< 10% /
10 years
30% / 71%
Intermediate
Risk
39% / 20%
High Risk
31% / 9%
10 – 20% /
10 years
Circulation
JAMA
 Imaging techniques
 Non imaging techniques
 Stress ECG (M 45 - 60 J)
 Biomarker
> 20% /
10 years
2000;101:111-116
2001;285:2486-97
+
intensive therapy /
risk factor
modification
Data from the Heinz Nixdorf Recall Study#
(incl. ATP III risk equivalents*)
Greenland et al.
•NCEP / ATP III
for healthy lifestyle
Greenland et al.
# Erbel et al.
Circulation 2001;104:1863-1867
Atherosclerosis 2007;197:662-72
Imaging of Coronary Subclinical Atherosclerosis
EKG
ECHOCARDIOGRAPHY
Non invasive Methods
SCINTIGRAPHY
PET
MRT
CT/CTA
Vasomotion testing
OCT IVUS/ICD IRS
Invasive Methods
0%
20%
CORONARY ANGIOGRAPHY
45%
50%
70%
90%
Di000802
Remodeling
modified according to Erbel R et al
originally ERBEL R
Life time
HERZ 32:351-55, 2007
HERZ 21: 75-77, 1996
Non-Invasive Imaging of Subclinical Coronary Atherosclerosis
using Computed Tomography
RVOT
No CAC
LAD
Ao
56 year M
LM
Score
49
CAC
51 year M
Score
2609
Score
115
64 year F
50 year M
Detection - Distribution – Quantification
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
Imaging of coronary
artery calcification as
a specific sign of
atherosclerosis
Agatston et al.
Hunold P et al
Schmermund et al .
- 0.94 Kappa value for interinstitutional variation
JACC 15:827-32, 1990
Radiology 226:14552,2003
Z Kardiol 92:I/385,2003
3. Step: Improving Risk Prediction for Coronary Events
using Signs of Coronary Subclinical Atherosclerosis by CT
Observed 5-yr Event Rate [%]
Events / # at Risk:
Crude Relative Risk:
FRS-adjusted* RR:
20
11 / 1287
1.0
1.0
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)
33 / 396
9.75 (4.97-19.11)
6.25 (3.01-13.00)
p=0.0007
16
p=0.002
12
p=0.13
8.3 %
8
3.5 %
4
1.5 %
0.9 %
0
0
<0-99
100-399
≥ 400
CAC Scoring
Erbel R et. al.
JACC 56:1397-406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Coronary Subclinical Atherosclerosis by CT
categories
Meta-analysis
HNR study
Meta-analysis
HNR study
Meta-analysis
HNR study
Meta-analysis
HNR study
Greenland et al. ACCF/AHA 2007
Erbel et al
Clinical expert consensus document
JACC 115:402, 2007
JACC 56:1397-406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Coronary Subclinical Atherosclerosis by CT
Rotterdam Study
Elias-Smale SE et al
JACC 56:1407-14, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis by CT
demonstrated by the Net Reclassification Improvement NRI
NRI: 20.8% (p=0.0004)
low
Erbel R et. al.
intermediate
high
JACC 56:1397-406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis by CT
demonstrated by the Net Reclassification Improvement NRI
Classification
according to FRS
Reclassification accounting
for CAC scores
Low
Intermed.
High
Total
25
12
0
37
0
9
0
9
0
16
29
45
25
37
29
91
2140
805
0
2945
0
293
0
293
0
168
469
637
2140
1266
469
3875
Coronary events
<10%
10-20%
>20%
Total Number
No coronary events
<10%
10-20%
>20%
Total
NRI: 20.8% (p=0.0004)
Erbel R et. al.
JACC 56:1397-406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis by CT
demonstrated by the Net Reclassification Improvement NRI
Comparison to the FRS 6-20% instead of 10-20%
Classification
according to
FRS 10-year event
rate
Reclassification accounting for
CAC scores
low
intermed.
high
Total
- low
- intermediate
- high
Total
without events
7
27
0
34
0
12
0
12
0
18
29
47
7
57
29
93
- low
- intermediate
- high
Total
933
1870
0
2803
0
479
0
479
0
246
508
754
933
2595
508
4036
with events
NRI = 30.6% (p<0.0001)
Erbel R et. al.
JACC 56:1397-406, 2010
3. Step: Improving Risk Prediction for Coronary Events
using Signs of Inflammation – a Biomarker
Prevalence of risk categories in Germany
Men / Women
< 10% /
10 years
30% / 71%
Low Risk
Intermediate
Risk
39% / 20%
High Risk
31% / 9%
10 – 20% /
10 years
> 20% /
10 years
Circulation
JAMA
2000;101:111-116
2001;285:2486-97
Detection of signs of
risk for CV events
Biomarker
+
intensive therapy /
risk factor
modification
Data from the Heinz Nixdorf Recall Study#
(incl. ATP III risk equivalents*)
Greenland et al.
•NCEP / ATP III
advice for
for healthy lifestyle
Greenland et al.
# Erbel et al.
Circulation 2001;104:1863-1867
Atherosclerosis 2007;197:662-72
Improvement of Risk Prediction for Coronary Events
using Biomarkers
Lipoprotein (a)
Univariate Analysis for
cardiac deah, AMI,
revascularisation
Homocystein
Cholesterol (TC)
n = 28.263
* n = 4.348
LDL-Cholesterol (LDLC)
TC/HDLC-Ratio
HS-CRP
*
Calcium Score
0
0.5
1
2
3
4
5
6
7
8
9
10
11
Relative Risk of Future Cardiovascular Events
Ridker PM et al
*O‘Malley PG et al
Circulation 103: 1813, 2001
Am J Cardiol 85: 945, 2001
3. Step: Improving Risk Prediction for Coronary Events
using the Biomarker – hs-CRP
Events / # at Risk:
Crude Relative Risk:
FRS-adjusted* RR:
Observed 5-yr Event Rate [%]
20
23 / 1387
1.0
1.0
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)
p=0.0006
16
12
8
p=0.70
4.1 %
4
1.7 %
1.8 %
0
<1.0 mg/L
1-3 mg/L
>3 mg/L
hsCRP Categories
Möhlenkamp S et al
JACC 2011 in press
Improvement of Risk Prediction for Coronary Events
using the Biomarker – hs-CRP vs CAC
mg/L
hs-CRP
Möhlenkamp S et al
J Am Coll Cardiol. 2011 ;57:1455-64
Improvement of Risk Prediction for Coronary Events
using the Biomarker – hs-CRP vs CAC
Sensitivity
1
0.75
AuROC-Curve:
FRS only: 0.691 (0.638-0.744)
0.5
FRS+hsCRP: 0.704 (0.652-0.757)
FRS+log2(CAC+1): 0.752 (0.700-0.804)
0.25
p=0.34
p=0.0074
p=0.014
p=0.19
FRS+hsCRP+log2(CAC+1): 0.760 (0.710-0.810)
0
0
0.25
0.5
0.75
1
1-Specificity
Möhlenkamp S et al
J Am Coll Cardiol. 2011 ;57:1455-64
Improvement of Risk Prediction for Coronary Events
using the Biomarker – hs-CRP
Net Reclassification Improvement
Classification
according to FRS
Reclassification accounting
for hsCRP scores
Low
Intermed.
High
Total
25
9
0
34
0
14
0
14
0
14
29
43
25
37
29
91
2140
388
0
2528
0
579
0
579
0
299
469
768
2140
1266
469
3875
Coronary events
<10%
10-20%
>20%
Total Number
No coronary events
<10%
10-20%
>20%
Total
NRI: 7.8% (p=0.14)
Möhlenkamp S et al
J Am Coll Cardiol. 2011 ;57:1455-64
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis and Biomarkers
Risk Marker / Factor:
Multiple Biomarker Score
NRI
26.7%
p-value
p=0.005
Reference
(Zethelius, NEJM 2008)*
14.6%
p=NS
(Melander, JAMA 2009)*
(Troponin I, NT-proBNP, Cystatin C, CRP)
Multiple Biomarker Score
(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.
Erbel R et al
JACC 54 :1209-1227, 2009
JACC 56 :1397- 406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis and Biomarkers
Risk Marker / Factor:
Multiple Biomarker Score
NRI
26.7%
p-value
p=0.005
Reference
(Zethelius, NEJM 2008)*
14.6%
p=NS
(Melander, JAMA 2009)*
12.1%
2.2%
p<0.001
p=0.006
(Pencina, Stat Med 2008)
(Cooney, EJCPR 2009)
p=NS
(Cooney, ESC 2009, Abstract)
p<0.0001
p<0.009
p<0.001
p <0.14
p=0.06
p=0.27
(Cook, Ann Int Med 2006)
(Wilson Cirulation 2008)
(Ridker, Circulation 2008)*
(Troponin I, NT-proBNP, Cystatin C, CRP)
Multiple Biomarker Score
(MR-proADM, NT-proBNP)
HDL-Cholesterol (Framingham)
HDL-Cholesterol (SCORE-Data)
Heart Rate
hsCRP (women)
hsCRP (men and women)
hsCRP (men)
hsCRP (total
HbA1c (men)
HbA1c (women)
1.1%
5.7%
11.8%
14.1%
7.8%
3.4%
- 2.2%
CAC (ATP III, FRS 10-20%, 6-10%) 18.8, 21.7%, 30.6%
modified from Cooney et al.
Erbel R et al
(Möhlenkamp JACC 2011)
(Simmons, Arch Int Med 2008)
(Simmons, Arch Int Med 2008)
p=0.0002 (Erbel JACC 2010)*
JACC 54 :1209-1227, 2009
JACC 56 :1397- 406, 2010
Improvement of Risk Prediction for Coronary Events
using Signs of Subclinical Atherosclerosis and Biomarkers
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.

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