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JA de Lemos, DA Morrow, SA Wiviott, P Jarolim, MA Blazing, MS Sabatine, RM Califf, E Braunwald

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).

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JA de Lemos, DA Morrow, SA Wiviott, P Jarolim, MA Blazing, MS Sabatine, RM Califf, E Braunwald

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  1. Serial Measurement of Monocyte Chemoattractant Protein-1 After Acute Coronary SyndromesResults 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

  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. MCP-1 and Outcomes After ACS MCP1 > 238 pg/mL p=0.001 Death or MI, % MCP1 < 238 pg/mL Days from Presentation with ACS 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 S40 Early Intensive Simvastatin 40 mg N = 4497 Delayed more Conservative Placebo Placebo Placebo Simvastatin 20 mg Mo 24 Mo 1 Mo 4 Randomization

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

  8. 10 Quartile 3 8 Quartile 4 6 Quartile 2 Mortality, % 4 Quartile 1 2 0 120 240 360 480 600 720 Days after Index ACS Event Baseline Levels of MCP-1 and Mortality p<0.0001

  9. Association Between MCP-1 and Primary Z Phase Endpoint P<0.0001 for trend 20 Quartile 4 Quartile 3 p<0.0001 Quartile 2 16 Quartile 1 12 CV death, MI, re-ACS, stroke (%) 8 4 0 0 120 240 360 480 600 720 Days After Index ACS Event

  10. Baseline MCP-1 and Mortality 8 MCP-1 > 238 pg/mL MCP-1 < 238 pg/mL 6 p<0.0001 Mortality (%) 4 2 0 120 240 360 480 600 720 Days Following Randomization

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

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

  13. Multivariable Analyses (Baseline) MCP-1 > 238 pg/mL Death MI Death/MI Death/MI/CHF Z phase primary Adjusted for age, sex, weight, prior MI, ACEI, DM, smoking, index dx, rx assignment, ClCr, LDL, CRP, BNP

  14. 5 MCP-1 > 238 pg/mL 4 MCP-1 < 238 pg/mL 3 Mortality (%) 2 1 120 240 360 480 600 720 Days Following Randomization 4 month MCP-1 and Mortality p<0.01

  15. Multivariable Analyses (4 mos) MCP-1 > 238 pg/mL Death MI Death/MI Death/MI/CHF Z phase primary Adjusted for age sex, DM, smoking, index dx, rx assignment, 4 mo LDL, CRP, BNP

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

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

  18. 0.25 0.5 1.0 2 HR Comparing Intensive vs Conservative Simvastatin Groups Baseline Death > 238 pg/mL < 238 pg/mL > 238 pg/mL < 238 pg/mL Death/MI/CHF Z phase Primary > 238 pg/mL < 238 pg/mL 4 mo Death > 238 pg/mL < 238 pg/mL > 238 pg/mL < 238 pg/mL Death/MI/CHF > 238 pg/mL < 238 pg/mL Z phase Primary

  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

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