Serial Measurement of Monocyte Chemoattractant Protein-1 After Acute
Coronary SyndromesResults From the A to Z Trial
JA de Lemos, DA Morrow, SA Wiviott, P Jarolim, MA Blazing, MS Sabatine,
RM Califf, E Braunwald
J J Am Coll Cardiol 2007;50:2117-24Am Coll Cardiol 2007;50:2117-24
Monocyte Chemoattractant Protein-1 (MCP-1)
• 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 figure
0 100 200 300
0%
5%
10%
15%
Days from Presentation with ACS
Dea
th o
r MI,
%
MCP1 > 238 pg/mL
MCP1 < 238 pg/mL
MCP-1 and Outcomes After ACS
p=0.001
de Lemos et al. Circulation 2003;107:690-5
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
Simvastatin 80 mg
Simvastatin 20 mg
Placebo
Randomization Mo 4 Mo 24Mo 1
Early Intensive
Delayed moreConservative
N = 4497
Simvastatin 40 mg
S40
Placebo Placebo
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
Baseline 4 months 12 months
MC
P-1
(pg/
mL)
P=0.005
Influence of Treatment Assignment
0
50
100
150
200
250
300
Placebo/Simvastatin 20 mg
Simvastatin 40/80 mg
Days after Index ACS Event
2
4
6
8
10
0 120 240 360 480 600 720
Mor
talit
y, %
Quartile 4
Quartile 3
Quartile 2
Quartile 1
Baseline Levels of MCP-1 and Mortality
p<0.0001
Association Between MCP-1 and Primary Z Phase Endpoint
CV
dea
th, M
I, re
-AC
S, s
troke
(%)
0 120 240 360 480 600 720
Days After Index ACS Event
Quartile 4
Quartile 3
Quartile 2
Quartile 1
P<0.0001 for trend
0
4
8
12
16
20
p<0.0001
Baseline MCP-1 and Mortality
2
4
6
8
0 120 240 360 480 600 720
MCP-1 < 238 pg/mLMCP-1 > 238 pg/mL
Mor
talit
y (%
)
Days Following Randomization
p<0.0001
0
2
4
6
8
10
CRP high CRP low> 15 mg/L < 15 mg/L
MCP-1 high
MCP-1 low
Mor
talit
y, %
MCP-1, CRP, and Mortality
p<0.0001
p<0.001
n=1029n=676
N=1266
n=924
0
5
10
15
20
BNP high BNP low> 80 pg/mL < 80 pg/mL
MCP-1 high
MCP-1 low
Mor
talit
y, %
MCP-1, BNP, and Mortality
p=0.08
n=253
n=353
n=1605
n=2030
P<0.0001
Multivariable Analyses (Baseline)
Adjusted for age, sex, weight, prior MI, ACEI, DM, smoking, index dx, rx assignment, ClCr, LDL, CRP, BNP
Death
MI
Death/MI
Death/MI/CHF
Z phase primary
MCP-1 > 238 pg/mL
0.25 0.5 1 2 4
1
2
3
4
5
120 240 360 480 600 720
MCP-1 < 238 pg/mLMCP-1 > 238 pg/mL
Mor
talit
y (%
)
Days Following Randomization
4 month MCP-1 and Mortality
p<0.01
Multivariable Analyses (4 mos)
Adjusted for age sex, DM, smoking, index dx, rx assignment, 4 mo LDL, CRP, BNP
Death
MI
Death/MI
Death/MI/CHF
Z phase primary
MCP-1 > 238 pg/mL
0.25 0.5 1 2 4
1.3
4.1
8.3
17.3
0
5
10
15
20
0 1 2 3Number of Elevated Biomarkers
Mor
talit
y %
n= 631 2017 1290 254
Adjusted HR 1 (ref) 2.3 4.4 7.6
p<0.0001
Multiple-Marker Strategy at BaselineMCP-1, CRP, BNP
1.23.1
5.7
13.3
0
5
10
15
0 1 2 3Number of Elevated Biomarkers
Mor
talit
y %
n= 851 1823 845 71Adjusted HR 1 (ref) 2.2 4.1 7.2
Multiple-Marker Strategy at 4 mos
p<0.0001
MCP-1, CRP, BNP
HR Comparing Intensive vs Conservative Simvastatin Groups
0.25 0.5 1.0 2
> 238 pg/mL< 238 pg/mL
> 238 pg/mL< 238 pg/mL
> 238 pg/mL< 238 pg/mL
> 238 pg/mL< 238 pg/mL
> 238 pg/mL< 238 pg/mL> 238 pg/mL< 238 pg/mL
Death
Death/MI/CHF
Z phase Primary
Death
Death/MI/CHF
Z phase Primary
4 mo
Baseline
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
