AHA / CDC Scientific Statement Markers of Inflammation and Cardiovascular Disease: Applications to Clinical and Public Health Practice Circulation January 28, 2003 Measurement of hs-CRP is an independent marker of risk and may be used at the

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AHA / CDC Scientific StatementMarkers of
Inflammation and Cardiovascular Disease
Applications to Clinical and Public Health
PracticeCirculation January 28,
2003Measurement of hs-CRP is an independent
marker of riskand may be used at the discretion
of the physician as partof global coronary risk
assessment in adults without known
cardiovascular disease. Weight of evidence favors
use, particularly among those judged at
intermediate risk byglobal risk assessment.
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Inflammation Thrombosis
Tissue factor
E-selectin
ICAM-1
VCAM-1
Thrombin
L-selectin
GPIb/X
MAC-1
Tissue factor
GP IIb/IIIa
CD40 ligand
CD40
P-selectin
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The Role of Platelets in Inflammation and Plaque
Stability
Activated platelets
Inflammatory modulators
CD40L Platelet-derived growth factor Platelet
factor 4 RANTES Thrombospondin Transforming
growth factor-? Nitric Oxide
Plaque rupture thrombosis
Libby P. Circulation 20011031718-1720
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Relative Risk of Cardiovascular Events Estimated
by Several Biochemical Markers
Relative Risk of Future CV Events
Lipoprotein(a)
Homocysteine
Total cholesterol
LDL-cholesterol
Apolipoprotein B
TCHDL-C ratio
hs-CRP
hs-CRP TCHDL-C ratio
0
1.0
2.0
4.0
6.0
adapted from Ridker PM, et al. N Engl J Med
2000342836-843
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Clinical Application of hs-CRP for Cardiovascular
Risk Prediction
gt100 mg/L
1 mg/L
3 mg/L
10 mg/L
Low Risk
Moderate Risk
Acute-Phase Response Ignore Value, Repeat Test
in 3 Weeks
High Risk
AHA/CDC Statement. Circulation 2003 107499511
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CRP Adds Prognostic Information at All Levels of
LDL-C and at All Levels of the Framingham Risk
Score
lt1.0
1.0-3.0
gt3.0
1.0-3.0
gt3.0
lt1.0
25
3
C-Reactive Protein (mg/L)
C-Reactive Protein (mg/L)
20
2
15
Relative risk
Multivariable relative risk
10
1
5
0
0
0-1
2-4
5-9
10-20
130-160
lt130
gt160
Framingham estimate of 10-year risk ()
LDL cholesterol (mg/dL)
Ridker et al. N Engl J Med 20023471557
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CRP Adds to the ATP-III Definition of the
Metabolic Syndrome (N 3097 with ATP-III
Metabolic Syndrome)
1.00
0.99
0.98
CRP lt 1 mg/L
CVD Event-Free Survival Probability
0.97
CRP 1-3 mg/L
0.96
CRP gt
3 mg/L
0.95
Years of Follow-Up
0
2
4
6
8
Ridker et al, Circulation 2003107391-397
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C-Reactive Protein Levels Predict All-Cause Death
After Ischemic Stroke
Kaplan-Meier survival curves based on
mortality from all causes adapted from Muir K.
Stroke 200030981-985
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Elevated CRP Predicts Risk of Cardiovascular
Events After First Stroke
Villa Pini Stroke Data Bank Study
CRP Level
70
gt 33 mg/L
n473
60
50
p lt0.001 log rank test
40
p lt0.001 chi-square for trend
MI, Stroke, or Vascular Death ()
5 - 33 mg/L
30
20
lt 5 mg/L
10
0
2
4
6
8
10
12
14
16
18
20
22
24
0
Months
Napoli M, et al. Stroke 2002 331763-1771
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Novel Risk Factors as Predictors of Peripheral
Arterial Disease
Lipoprotein(a) Homocysteine VCAM-1 Fibrinogen
LDL-C ICAM-1 hs-CRP TCHDL-C CRP TC HDL-C
0 1.0 2.0 4.0 6.0
Relative Risk of Incident Peripheral
Arterial Disease (Adjusted for age, smoking, DM,
HTN, family history, exercise level, and BMI)
Ridker et al. JAMA 20012852481-2485
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CRP Level Predicts Prevalence of Multiple
Coronary Plaques in Patients with Unstable Angina
Patients by CRP Tertile (mg/L)
Patients with Multiple Plaques gt2(p lt 0.001)
Patients ()
n71
n78
n79
Zairis MN, et al. Atherosclerosis 2002164355-359
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Clopidogrel Reduces ADP-Induced Expression of
Platelet-Derived CD40L
ASA 100 uM in vitro clopidogrel 75 mg/d for 7
days
Hermann A, et al. Platelets 20011274-82
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Clopidogrel Therapy Reduces the Risk Associated
With Elevated Baseline CRP Status
Death or MI by Day 30 in Patients Undergoing PCI
With Stenting
No thienopyridinepretreatment
24 n74
25
Thienopyridinepretreatment
20
13 n295
15
10.2 n136
Percent
10 n565
10
58 RRR p 0.002
5
0
Total population0-lt1.1 mg/dL
Highest quartilegt1.1 mg/dL
Chew DP, et al. Am J Cardiol 200188672-674
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Clopidogrel Pretreatment Reduces CRP levels in
Patients Undergoing PCI
No Clopidogrel Pretreatment n533
CRP levels measured 24 hours post-PCI
Clopidogrel Pretreatment n282
0.43 mg/dL
0.38 mg/dL
0.39 mg/dL
p 0.026
p 0.89
CRP Level (mg/dL)
0.15 mg/dL
Baseline CRP Pre-PCI
CRP Level Post-PCI
Vivekananthan DP, Bhatt DL, et al. ACC Scientific
Sessions. Chicago 2003.
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Assays of Inflammatory Markers for Potential
Clinical Use
WHO Standard
Analyte
Stability
Availability
Precision
s-CAMs
Unstable(unless frozen)
Limited
No
CV lt 15
Cytokines
Unstable(unless frozen)
Few
IL-6
CV lt 15
Acute-Phase Reactants Fibrinogen
Unstable(unless frozen)
Many
Yes
CV lt 8
SAA
Stable
One
Yes
CV lt 9
hsCRP
Stable
Many
Yes
CV lt 10
WBC
Stable
Many
Yes
CV lt 3
AHA/CDC Statement. Circulation 2003 107499511
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AHA/CDC Recommendations for Clinical and Public
Health Practice
Class I Should be performed Class II
Conflicting evidence/opinion a Weight in
favor of usefulness/efficacy b
Usefulness/efficacy less well established Class
III Should not be performed
Laboratory Tests

• Of current inflammatory markers identified,
  hs-CRP has the analyte assay characteristics
  most conducive to use in practice (Class IIa,
  Level of Evidence B).
• Other inflammatory markers should not be measured
  for determination CV risk in addition to hs-CRP
  (Class III, Level of Evidence C)

AHA/CDC Statement. Circulation 2003 107499511
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AHA/CDC Recommendations for Clinical and Public
Health Practice
Clinical Practice

• Measurement of hs-CRP is an independent marker of
  risk and, in those judged at intermediate risk by
  global risk assessment (10-20 CHD/yr) may help
  direct further evaluation therapy in primary
  prevention of CHD (Class IIa, Level of Evidence
  B)
• Measurement of hs-CRP may be used at discretion
  of the physician as part of global risk
  assessment in adults without known CVD (Class
  IIb, Level of Evidence C)
• The benefits of such therapy based on these
  strategies remain uncertain

AHA/CDC Statement. Circulation 2003 107499511
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AHA/CDC Recommendations for Clinical and Public
Health Practice
Clinical Practice / Population Science

• Benefit of strategy of evaluation and therapy
  guided byhs-CRP remains uncertain
• hs-CRP levels may be useful in motivating
  patients to improve lifestyle behaviors (Class
  IIb, Level of Evidence C)
• The entire adult population should not be
  screened for hs-CRP for purposes of
  cardiovascular risk assessment (Class III, Level
  of Evidence C)
• ADDITIONAL CLINICAL EVIDENCE REGARDING THE
  POTENTIAL BENEFITS HARM, AS WELL AS
  COST-EFFECTIVENESS OF SUCH SCREENING, IS NEEDED

AHA/CDC Statement. Circulation 2003 107499511
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AHA/CDC Recommendations for Clinical and Public
Health Practice
Clinical Practice

• In patients with documented CAD or ACS, hs-CRP
  may be useful as an independent marker of
  prognosis (death, MI, restenosis after PCI)
  (Class IIa, Evidence C)
• Application of secondary prevention measures
  (Class III, Level of Evidence A) or management
  guidelines for ACS should not be dependent on
  hs-CRP levels (Class III, Level of Evidence C)

AHA/CDC Statement. Circulation 2003 107499511
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AHA/CDC Recommendations for Clinical and Public
Health Practice
Laboratory Testing

• Should ordinarily be done 2x (averaging results)
  2 weeks apart (fasting/non-fasting), in
  metabolically stable patients. If hs-CRP gt10 mg/L
  repeat assess for sources of infection or
  inflammation (Class IIa, Evidence B)
• hs-CRP results should be expressed as mg/L only
  (Class I, Level of Evidence A)
• hs-CRP (using standardized assays), categorize
  as
• Average Level Relative Risk Category
  lt 1 mg/L Low 1.0 3.0 mg/L Average
  gt 3.0 mg/L High

AHA/CDC Statement. Circulation 2003 107499511