MCP-1

Report
Serial Measurement of Monocyte
Chemoattractant Protein-1 After Acute
Coronary Syndromes
Results From the A to Z Trial
J Am Coll Cardiol 2007;50:2117-24
JA de Lemos, DA Morrow, SA Wiviott,
P Jarolim, MA Blazing, MS Sabatine,
RM Califf, E Braunwald
Monocyte Chemoattractant Protein-1 (MCP-1)
MCP-1 figure
• Transgenic MCP-1 mice:  athero
• Plasma MCP-1 assoc with ASHD risk factors
• older age, DM, HTN, Fam Hx CAD,  LDL,  renal fxn
• Modified by preventive rx (statin, TZD, etc)
MCP-1 and Outcomes After ACS
MCP1 > 238 pg/mL
Death or MI, %
15%
p=0.001
10%
MCP1 < 238 pg/mL
5%
0%
0
100
200
Days from Presentation with ACS
de Lemos et al. Circulation 2003;107:690-5
300
Objectives
• Evaluate the Prognostic Value of MCP-1 in
Patients following ACS
• Serial measurement in acute and chronic phase
• Account for standard risk variables
• Account for emerging biomarkers (CRP, BNP)
• Determine the influence of statin therapy on
MCP-1 levels
• Determine whether MCP-1 helps to identify
candidates for more intensive statin rx
Study Design
S40
Early
Intensive
Simvastatin 80 mg
Simvastatin 40 mg
N = 4497
Delayed more
Conservative
Placebo
Placebo
Randomization
Placebo
Mo 1
Simvastatin 20 mg
Mo 4
Mo 24
Methods
• MCP-1 measured from baseline (n=4244), 4 mo
(n=3603) and 12 mo samples (n=2950)
• BNP (Bayer) and CRP (Denka Seiken) measured
on baseline and 4 mo samples
• Endpoints compared using MCP-1 quartiles and
prespecified threshold of 238 pg/mL
• Landmark analysis used to evaluate association
between 4 month lab values and subsequent
outcomes
Influence of Treatment Assignment
300
250
MCP-1 (pg/mL)
P=0.005
200
150
100
Placebo/Simvastatin 20 mg
Simvastatin 40/80 mg
50
0
Baseline
4 months
12 months
Baseline Levels of MCP-1 and Mortality
10
8
Mortality, %
Quartile 3
p<0.0001
Quartile 4
6
Quartile 2
4
Quartile 1
2
0
120
240
360
480
600
Days after Index ACS Event
720
CV death, MI, re-ACS, stroke (%)
Association Between MCP-1 and
Primary Z Phase Endpoint
P<0.0001 for trend
20
Quartile 4
Quartile 3
p<0.0001
16
Quartile 2
Quartile 1
12
8
4
0
0
120
240
360
480
Days After Index ACS Event
600
720
Baseline MCP-1 and Mortality
Mortality (%)
8
MCP-1 > 238 pg/mL
MCP-1 < 238 pg/mL
6
p<0.0001
4
2
0
120
240
360
480
Days Following Randomization
600
720
MCP-1, CRP, and Mortality
p<0.0001
Mortality, %
10
p<0.001
8
N=1266
6
n=924
4
MCP-1 high
2
n=1029
n=676
0
CRP high
> 15 mg/L
CRP low
< 15 mg/L
MCP-1 low
MCP-1, BNP, and Mortality
p=0.08
Mortality, %
20
15
n=353
P<0.0001
10
n=2030
MCP-1 high
5
n=253
n=1605
0
BNP high
> 80 pg/mL
BNP low
< 80 pg/mL
MCP-1 low
Multivariable Analyses (Baseline)
MCP-1 > 238 pg/mL
Death
MI
Death/MI
Death/MI/CHF
Z phase primary
0.25
0.5
1
2
4
Adjusted for age, sex, weight, prior MI, ACEI, DM, smoking,
index dx, rx assignment, ClCr, LDL, CRP, BNP
4 month MCP-1 and Mortality
5
MCP-1 > 238 pg/mL
Mortality (%)
4
MCP-1 < 238 pg/mL
3
p<0.01
2
1
120
240
360
480
Days Following Randomization
600
720
Multivariable Analyses (4 mos)
MCP-1 > 238 pg/mL
Death
MI
Death/MI
Death/MI/CHF
Z phase primary
0.25
0.5
1
2
4
Adjusted for age sex, DM, smoking, index dx, rx assignment,
4 mo LDL, CRP, BNP
Multiple-Marker Strategy at Baseline
MCP-1, CRP, BNP
20
17.3
p<0.0001
Mortality %
15
10
8.3
4.1
5
1.3
0
0
1
2
3
Number of Elevated Biomarkers
n=
Adjusted HR
631
2017
1 (ref)
2.3
1290
254
4.4
7.6
Multiple-Marker Strategy at 4 mos
MCP-1, CRP, BNP
15
13.3
Mortality %
p<0.0001
10
5.7
5
3.1
1.2
0
0
1
2
3
Number of Elevated Biomarkers
n=
Adjusted HR
851
1 (ref)
1823
2.2
845
4.1
71
7.2
HR Comparing Intensive vs Conservative
Simvastatin Groups
Baseline
Death
> 238 pg/mL
< 238 pg/mL
Death/MI/CHF
> 238 pg/mL
< 238 pg/mL
Z phase Primary
> 238 pg/mL
< 238 pg/mL
Death
> 238 pg/mL
< 238 pg/mL
Death/MI/CHF
> 238 pg/mL
< 238 pg/mL
> 238 pg/mL
< 238 pg/mL
Z phase Primary
0.25
0.5
1.0
2
4 mo
Conclusions
• In pts stabilized following ACS,  MCP-1
• Associated with  risk for death and major CV
events
• Independent of standard clinical variables, LDL,
CRP, and BNP
• Similar findings in acute and chronic phase
• Statins had only a modest effect on MCP-1
levels
• MCP-1 did not predict benefit from early
intensive statin rx
• MCP-1 merits further study
• as a risk marker in ACS
• as a target for therapy

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