HIGH SENSITIVITY C-REACTIVE PROTEIN IN CARDIOVASCULAR DISEASE AND MORTALITY

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HIGH SENSITIVITY C-REACTIVE PROTEIN IN
CARDIOVASCULAR DISEASE AND MORTALITY

• Gary A. Lopez, M.D.
• Makati Medical Center
• Asian Hospital and Medical Center

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• Cardiovascular disease is the most frequent cause
  of mortality in the Philippines , the U.S., and
  many parts of the world.
• Most events caused by acute coronary events from
  coronary artery disease

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ATHEROTHROMBOSIS LEADS TO CARDIAC AND VASCULAR
EVENTS
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COEXISTENCE OF ATHEROSCLEROTIC VASCULAR DISEASE
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Pathology of Acute Coronary Syndrome
Plaque Rupture
Plaque Erosion
Calcified Nodules
Luminal Thrombosis
Acute Coronary Syndrome
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Type of Vulnerable Plaque Frequency Pathological Findings
Plaque Rupture 55 60 Numerous neutrophils, Macrophages and monocyte infiltration of thrombus
Plaque Erosion 30 35 Few or absent macrophages and lymphocytes
Calcified Nodule 2 7 Fibrin in between bony spicules along with osteoclasts and inflammatory cells
Virnani et al., JACC vol. 47, no. 8, 2006
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FORMATION OF THE FIBROFATTY PLAQUE
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FORMATION OF THE YOUNG ATHEROSCLEROTIC LESION
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MATURATION OF THE ATHEROSCLEROTIC PLAQUE
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AVERAGE COMPOSITION OF ADVANCED CORONARY PLAQUE
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• High-Risk, Vulnerable and Thrombosis-Prone Plaque
• - synonyms to describe a plaque that is at
  increased risk of thrombosis and rapid stenosis
  progression
• Inflamed Thin-cap Fibroatheroma
• - an inflamed plaque with a thin cap covering
  a lipid-rich, necrotic core. Suspected to be a
  high risk/vulnerable plaque.
• Vulnerable patient
• - a patient at high risk (vulnerable/prone) to
  experience a cardiovascular ischemic event due to
  a high atherosclerotic burden, high
  risk/vulnerable plaques, and/or thrombogenic
  blood.

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NON-INVASIVE TESTS TO IDENTIFY HIGH-RISK CORONARY
DISEASE (gt10 1-YEAR RISK OF CARDIAC EVENTS)

• 1. MRI of the coronary arteries
• 2. Multislice (64-slice) CT angiography of the
  coronary arteries with calcium scoring
• 3. Myocardial perfusion imaging using
  radionuclide techniques.
• 4. Positive emission tomography.

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CORONARY ANGIOGRAPHY

• An invasive cardiac diagnostic procedure using
  catheterization techniques and fluoroscopic
  visualization.
• Should be performed in asymptomatic high-risk
  patients.
• Provide risk stratification to alter therapy.

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C- REACTIVE PROTEIN

• A circulating pentraxin
• Produced predominantly in the liver as part of
  the acute phase response
• Expressed in smooth muscle cells within diseased
  atherosclerotic arteries
• Plays a major role in human innate immune
  response
• Provides a stable plasma biomarker for low-grade
  systemic inflammation

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C-REACTIVE PROTEIN

• Composed of five 23 kD subunits
• Has a half-life of 19 hours
• Neither consumed nor produced during the
  reaction.
• Ideally 2 assays, averaged, fasting or
  nonfasting, and optimally 2 weeks apart, provide
  a more stable level of this marker.

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C-REACTIVE PROTEIN

• Stable for over long periods of time
• Has no circadian rhythm
• Not affected by food intake
• Therefore screening can be done on an outpatient
  basis at the time of cholesterol evaluation.

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• Cost of high-sensitivity C-reactive protein at
  Makati Medical Center
• 925.00 pesos

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MECHANISMS OF HSCRP ELEVATION IN RELATION TO
ATHEROTHROMBOTIC EVENTS

• Unknown
• Theories
• 1. Inflammation of atherosclerotic plaques
  leading to HSCRP elevation
• 2. HSCRP may contribute to pathogenesis of
  atherosclerosis due to interaction with lipids,
  lipoproteins, complement and coagulation
• 3. HSCRP is detected in atherosclerotic
  plaques

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C-REACTIVE PROTEIN

• Mechanisms of influencing direct vascular
  vulnerability
• 1. increased expression of endothelial
  PAI-1.
• 2. enhanced expression of adhesion molecules
• 3. reduced endothelial nitric oxide
  bioactivity.
• 4. altered LDL uptake by macrophages
• 4. colocalization with complement within
  atherosclerotic lesions.
• 5. inhibition of intrinsic fibrinolysis

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THE INFLAMMATORY PATHWAY
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USES OF ELEVATED HSCRP

• Neonatal medicine - infection
• Atherosclerotic and coronary heart disease
• Osteoarthritis

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CONDITIONS ASSOCIATED WITH MAJOR ELEVATION OF
SERUM CRP

• Infections
• Allergic complications of infection
• Rheumatic fever
• Erythema nodosum leprosum
• Inflammatory disease
• Rheumatoid arthritis
• Juvenile chronic arthritis
• Ankylosing spondylitis
• Psoriatic arthritis
• Systemic vasculitis
• Polymyalgia rheumatica
• Reiters disease
• Crohns disease
• Familial Mediterranean fever
• Necrosis
• Myocardial infarction

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ROLE OF INFECTION IN ATHEROTHROMBOSIS

• 1. Clamydia , Helicobacter, Herpes simplex virus
  and Cytomegalovirus
• -- lead to systemic inflammation.
• -- lead to increased risk of
  cardiovascular events.
• 2. Clamydia and viral species have been
  identified in atheromatous lesions.

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• Need 2-3 weeks to check HSCRP in patients with
  injury or infection due to marked degree of
  inflammation.

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• Hormonal replacement therapy
• may augment levels of HSCRP

Cushman et al, Citculation 100717-7221999
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NON-PHARMACOLOGIC METHODS TO REDUCE HSCRP

• 1. WEIGHT REDUCTION
• 2. EXERCISE

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VALUE OF HSCRP MEASUREMENTS

• Conventional CRP assays cannot quantify serum
  proteins less than 5 mg/l.

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HSCRP gt 2.5 mg/liter

• Two to five-fold increased risk of suffering a
  coronary event in the future in patients with
  angina or in healthy normal adult population.
• May predict progression of atherothrombotic
  events in cerebrovascular and peripheral vascular
  disease.

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HSCRP gt 3 mg/liter

• Poor outcome in patients with severe unstable
  angina ( increased risk of death, acute
  myocardial infarction, or need for urgent
  revascularization intervention).
• Predicts early reocclusion in patients undergoing
  PCI.

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Your blood pressure and cholesterol are fine,
but your hsCRP
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USE OF HSCRP IN PRIMARY AND SECONDARY PREVENTION

• More than 24 prospective epidemiologic primary
  prevention studies evaluated the role of hsCRP as
  a determinant of vascular risk all reported
  positive findings.
• 10 of these studies were powered to evaluate the
  risk prediction role of hsCRP beyond that
  associated with traditional factors included in
  global assessment algorithms such as the
  Framingham Risk Score.

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HSCRP HAS STRONG PREDICTIVE VALUE IN

• 1. currently healthy men
• 2. currently healthy women
• 3. elderly people
• 4. high-risk smokers
• 5. stable and unstable angina
• 6. prior myocardial infarction

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ADDITIVE VALUE OF HSCRP AFTER ADJUSTMENT FOR RISK
FACTORS
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RELATIVE RISKS OF FUTURE CV EVENTS ACCORDING TO
BASELINE LEVELS OF HSCRP
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PROSPECTIVE STUDIES RELATING BASELINE HSCRP
LEVELS TO THE RISK OF FIRST CV EVENTS
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ADDITIVE VALUE OF HSCRP OVER TOTAL CHOLESTEROL,
HDL-C AND APO BAPO A RATIO
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Ridker et al, Womens Health Study , NEJM, 2002
347 1557-65
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Ridker et al,Clinical application of CRP for CV
disease detection and prevention,Circulation
107363,2003
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GUSTO IV ACS Trial
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PROGNOSTIC UTILITY OF HSCRP, TROPONIN, AND BNP IN
ACUTE CORONARY ISCHEMIA
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• Baseline levels of HSCRP associate with increased
  risk of developing Type 2 diabetes mellitus.
• Prediction of vascular events is beyond the
  components of the metabolic syndrome or presence
  of frank diabetes.

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NATIONAL HEALTH AND NUTRITION EVALUATION SURVEY
(NHANES)
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Rotterdam Scan Study

• Higher HSCRP levels are associated with the
  presence and progression of cerebral white matter
  lesions in the periventricular and subcortical
  regions.
• Data implies small vessel disease progression.

Van Dijk EJ et al, Circulation, 2005112900-5
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• Recent observations
• 1. Statins lower CRP in a manner largely
  independent of LDL-C reduction.
• 2. Efficacy of statin therapy may be related to
  the underlying level of vascular inflammation as
  detected by HS-CRP.

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CHOLESTEROL AND RECURRENT EVENTS (CARE) TRIAL

• Risk reduction with Pravastatin was greater in
  patients with elevated HSCRP
• Pravastatin significantly reduced elevated HSCRP
  levels over a 5-year period

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PRAVASTATIN OR ATORVASTATIN EVALUATION AND
INFECTION THERAPY-THROMBOLYSIS IN MYOCARDIAL
INFARCTION 22 TRIAL (PROVE IT-TIMI 22)

• 1. level of HS-CRP achieved after initiation of
  statin therapy is as important as LDL-C for
  subsequent vascular events.
• 2. best overall survival was seen not only with
  patients whose LDL-C was lowered to lt70 mg/dl but
  also whose HS-CRP lowered lt 2 mg/l.
• 3. this result was present regardless of statin
  regimen used.
• 4. measuring and monitoring of HS-CRP following
  initiation of statin therapy may be required to
  maximize benefit similar to use of LDL-C.

Ridker et al, NEJM, 2005 352 20-8
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PROVE IT - TIMI 22 CUMULATIVE RATE OF RECURRENT
M.I. OR DEATH AMONG STATIN-TREATED PATIENTS
ACCORDING TO ACHIEVED LEVELS OF LDL-C AND HSCRP
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PROVE IT - TIMI 22 RATE OF RECURRENT M.I OR
DEATH AMONG STATIN-TREATED PATIENTS ACCORDING TO
LDL-C AND HSCRP AFTER 30 DAYS
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REVERSAL study

• Patients were randomized to moderate lipid
  lowering with Pravastatin 40 mg or intensive
  lipid lowering with Atorvastatin 80 mg for 18
  months.
• Measurement of atherosclerotic burden by IVUS was
  carried out during baseline catheterization and
  at study completion. 502 patients completed the
  trial, 249 on Pravastatin and 253 for
  Atorvastatin. The 2 treatment groups were well
  matched ave. age was 56 yrs, about 70 were
  male, and 20 were diabetic. Baseline
  LDL-cholesterol was 150 mg/dl in both groups,
  triglycerides 197 mg/dl, and C-reactive protein
  (CRP) approximately 3 mg/dl.
• By the end of the treatment group, LDL-chol was
  significantly lower among patients who had been
  randomized to the Atorvastatin group.

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REVERSAL STUDY Secondary Endpoints
Endpoints Pravastatin ( n249) Atorvastatin ( n253) P value, Pravastatin vs. Atorvastatin
Change in total Atheroma Volume (mm3) 4.4 -0.9 .02
P value vs baseline .01 .72 --
Change in obstructive Volume () 1.6 0.2 .0002
P value vs baseline .0001 .18 --
Change in hsCRP () -5.2 -36.4
Wilcoxon signed rank test Wilcoxon rank sum
test
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ASSESSMENT OF THE CLINICAL UTILITY OF NOVEL
MARKERS OF CV RISK
Marker Assay conditions standardized? Prospective studies consistent? Additive to total cholesterol and HDL-C? Additive to Framingham risk?
Lipoprotein (a) - /- /- -
Homocysteine /- -
Tissue plasminogen activator and PAI-1 /- /- -
Lipoprotein density - /- - -
Fibrinogen - -
High-sensitivity CRP
Ridker et al, Risk Factors for Atherothrombotic
Disease, 2005, 939-54
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ACC/AHA CLASSIFICATIONS

• Class 1
• Conditions for which there is evidence
  and/or general agreement that a given procedure
  or treatment is useful and effective.
• Class II
• Conditions for which there is conflicting
  evidence and/or a divergence of opinion about the
  usefulness/efficacy of a procedure or treatment.
• Class IIa Weight of evidence/opinion is in
  favor of usefulness/efficacy
• Class IIb Usefulness/efficacy is less well
  established by evidence/opinion.
• Class III
• Conditions for which there is evidence
  and/or general agreement that a procedure
  /treatment is not useful/effective and in some
  cases may be harmful.

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ACC/AHA GUIDELINES FOR THE MANAGEMENT OF PATIENTS
WITH UNSTABLE ANGINA AND NON-ST-SEGMENT ELEVATION
MYOCARDIAL INFARCTION Nov, 2002

• II. Initial evaluation and Management
• B. Early Risk Stratification Recommendations
• Class IIb
• 1. C-reactive protein (CRP) and other markers
  of inflammation should be measured.

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CENTERS FOR DISEASE CONTROL AND PREVENTION /
AMERICAN HEART ASSOCIATION

• MARKERS OF INFLAMMATION AND CARDIOVASCULAR
  DISEASE A STATEMENT FOR HEALTHCARE PROFESSIONALS
• It is reasonable to measure HSCRP as an adjunct
  to the major risk factors to further assess
  absolute risk for coronary disease primary
  prevention optional.
• HSCRP measurement appears to be best employed to
  detect enhanced absolute risk in persons in whom
  multiple risk factor scoring projects a 10-year
  CHD risk in the range of 10 to 20 -
  intermediate risk.
• Pearson et al,
• Circulation, 2003 107449

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CDC/AHA ISSUES ON HSCRP

• 1. When and in whom should HSCRP be used?
• 2. What is the purpose for its measurement and
  the likelihood that further diagnostic and
  therapeutic plans change on the basis of tests
  results?
• 3. No clinical trials have been completed in
  which a population has been randomly allocated to
  HSCRP screening and both groups followed up
  prospectively to determine the benefits and harms
  of the screening.
• 4. Few data on the cost-effectiveness of
  screening with HSCRP, taking into account further
  testing and treatment of persons classified as
  being at low risk.

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CDC/AHA RECOMMENDATIONS

• 1. HSCRP gt 3.0 mg/L (high risk) may allow
  intensification of medical therapy to further
  reduce the risk and to motivate patients to
  improve their lifestyle or comply with
  medications prescribed to lower their risk.
• 2. Low risk individuals (lt10 in 10 years) will
  unlikely to have a high risk (gt20) identified
  thru HSCRP testing.
• 3. High risk individuals (gt20 in 10 years) or
  with established atherosclerotic disease
  generally should be treated intensively
  regardless of their HSCRP levels. (limited use of
  HSCRP in secondary prevention).

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CDC/AHA RECOMMENDATIONS

• 4. In patients with stable coronary disease or
  acute coronary syndromes, HSCRP measurement may
  be useful as an independent marker for assessing
  likelihood of recurrent events, including death,
  myocardial infarction, or restenosis after PCI.
• 5. Secondary preventive interventions with proven
  efficacy should not be dependent on HSCRP levels.
• 6. Serial testing of HSCRP should not be used to
  monitor effects of treatment.

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• The CDC/AHA Workshop identified CRP as the
  current analyte of choice , but do not support
  its use in risk prediction or patient management
  at this point in time.

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ISSUES ON HS-CRP

• No firm data to date that lowering CRP levels per
  se will lower vascular risk.
• It remains controversial whether CRP plays a
  direct causal role in atherogenesis.

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CONCLUSION

• Data for high-sensitivity C-reactive protein
  provides evidence that biomarkers beyond those
  taditionally used for vascular risk detection and
  monitoring can play important clinical roles in
  prevention and treatment.

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• Thank You