1. Serial Measurement of Monocyte Chemoattractant Protein-1 After Acute Coronary Syndromes Results From the A to Z Trial JA de Lemos, DA Morrow, SA Wiviott, P Jarolim, MA Blazing, MS Sabatine, RM Califf, E Braunwald J Am Coll Cardiol 2007;50:2117-24

2. 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

3. Days from Presentation with ACS Death or 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

4. 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

5. Study Design Simvastatin 80 mg Simvastatin 20 mg Placebo Randomization Mo 4 Mo 24 Mo 1 Early Intensive Delayed more Conservative N = 4497 Simvastatin 40 mg S40 Placebo

6. 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

7. Baseline 4 months 12 months MCP-1 (pg/mL) P=0.005 Influence of Treatment Assignment

8. Days after Index ACS Event 2 4 6 8 10 0120240360480600720 Mortality, % Quartile 4 Quartile 3 Quartile 2 Quartile 1 Baseline Levels of MCP-1 and Mortality p<0.0001

9. Association Between MCP-1 and Primary Z Phase Endpoint CV death, MI, re-ACS, stroke (%) 0120240360480600720 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

10. Baseline MCP-1 and Mortality 2 4 6 8 0120240360480600720 MCP-1 < 238 pg/mL MCP-1 > 238 pg/mL Mortality (%) Days Following Randomization p<0.0001

11. CRP high CRP low > 15 mg/L < 15 mg/L MCP-1 high MCP-1 low Mortality, % MCP-1, CRP, and Mortality p<0.0001 p<0.001 n=1029 n=676 N=1266 n=924

12. BNP high BNP low > 80 pg/mL < 80 pg/mL MCP-1 high MCP-1 low Mortality, % MCP-1, BNP, and Mortality p=0.08 n=253 n=353 n=1605 n=2030 P<0.0001

13. 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

14. 1 2 3 4 5 120240360480600720 MCP-1 < 238 pg/mL MCP-1 > 238 pg/mL Mortality (%) Days Following Randomization 4 month MCP-1 and Mortality p<0.01

15. 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

16. 0 1 2 3 Number of Elevated Biomarkers Mortality % n= 631 2017 1290 254 Adjusted HR 1 (ref) 2.3 4.4 7.6 p<0.0001 Multiple-Marker Strategy at Baseline MCP-1, CRP, BNP

17. 0 1 2 3 Number of Elevated Biomarkers Mortality % n= 851 1823 845 71 Adjusted HR 1 (ref) 2.2 4.1 7.2 Multiple-Marker Strategy at 4 mos p<0.0001 MCP-1, CRP, BNP

18. 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

19. 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