crp and inflammatory markers - national-academies.org/media/files/activity files/research... · crp...

Christie M. Ballantyne, M.D.Christie M. Ballantyne, M.D.Center for Cardiovascular Disease PreventionCenter for Cardiovascular Disease PreventionMethodist Methodist DeBakeyDeBakey Heart & Vascular CenterHeart & Vascular Center

Baylor College of MedicineBaylor College of MedicineHouston, TexasHouston, Texas

CRP and Inflammatory MarkersCRP and Inflammatory Markers

66 year old nondiabetic Hispanic woman with history of borderline hypertension, not on meds

Height 5'6"Waist 36"Weight 188 lbBMI 30.3BP 145/83

CaseCase

Smoker NoTC 231TG 240HDL 57LDL 126

Framingham Risk ScoreFramingham Risk Score

5% 105% 10--year riskyear risk1717TotalTotal33SBP SBP 00HDLHDL--C C 00NonsmokerNonsmoker22TC TC

1212Age 66Age 66

Expert Panel on Detection, Evaluation, and Treatment of High BloExpert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in od Cholesterol in Adults. Adults. JAMAJAMA 2001;285:24862001;285:2486--2497.2497.

•• Improve global risk assessment, Improve global risk assessment, particularly in intermediateparticularly in intermediate--risk patientsrisk patients

•• Guide selection or intensity of therapyGuide selection or intensity of therapy•• Provide target of therapy if risk factor Provide target of therapy if risk factor

and not just markerand not just marker

How Can Biomarkers be Used to How Can Biomarkers be Used to Improve Patient Care?Improve Patient Care?

Overview of Efforts to Identify Overview of Efforts to Identify Biochemical and Molecular Markers Biochemical and Molecular Markers for Atherosclerosis Risk Stratificationfor Atherosclerosis Risk Stratification

•• Surveys for identification of risk factors:Surveys for identification of risk factors:–– large epidemiological trials and clinical large epidemiological trials and clinical

event trialsevent trials•• Candidate molecules based upon biologyCandidate molecules based upon biology

–– Inflammation and thrombosisInflammation and thrombosis

CC--Reactive ProteinReactive Protein•• PentamericPentameric polypeptide produced by hepatocytes in polypeptide produced by hepatocytes in

response to inflammatory cytokines such as ILresponse to inflammatory cytokines such as IL --66•• AAcutecute--phase protein involved in a variety of disorders phase protein involved in a variety of disorders

that are mediated by inflammatory processesthat are mediated by inflammatory processes•• Stimulates secretion of Stimulates secretion of proinflammatoryproinflammatory cytokines cytokines

(e.g., IL(e.g., IL--6, TNF6, TNF--αα, adhesion molecules, endothelin, adhesion molecules, endothelin --1, 1, and MCPand MCP--1) by endothelial cells1) by endothelial cells

•• Can bind to apolipoprotein BCan bind to apolipoprotein B––containing lipoproteins containing lipoproteins and and opsonizeopsonize LDL for uptake by human monocyteLDL for uptake by human monocyte--derived macrophagesderived macrophages

•• Predictive of cardiovascular events in prospective Predictive of cardiovascular events in prospective studiesstudies

0

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2

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1

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< 1 1 - 3 > 3

WHS

0

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< 1 1 - 3 > 30

1

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< 1 1 - 3 > 3

ARICMONICAPHS

0

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< 1 1 - 3 > 30

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< 1 1 - 3 > 3

HPFSNHS

0

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1 2 3

Reykjavik*

Fram

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Rel

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hsCRPhsCRP Adds Prognostic Information Beyond the Framingham Adds Prognostic Information Beyond the Framingham Risk Score in ALL Major Cohorts EvaluatedRisk Score in ALL Major Cohorts Evaluated

0

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CHS

0

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EPIC-Norfolk

1997 2002 2004 2004 2004

2004 2004 2005 2005

0

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2005

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5

10

15

20

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0–1 2–4 5–9 ≥10 130–160

Multiv

aria

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Rel

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isk

Framingham Estimate of 10-yr Risk, %

Ridker PM et al. N Engl J Med 2002;347:1557–1565.

MultivariableMultivariable--Adjusted Relative Risk for First Adjusted Relative Risk for First CV Event by CRP and Framingham Risk Score CV Event by CRP and Framingham Risk Score and by CRP and LDLand by CRP and LDL--C Categories: C Categories: WHSWHS

LDL-C, mg/dL

0

1

2

3

<130 >160

<1.01.0–3.0>3.0

Slide Source:Slide Source:Lipids Online Slide LibraryLipids Online Slide Librarywww.lipidsonline.orgwww.lipidsonline.org

http://www.lipidsonline.org

http://www.lipidsonline.org

LipoproteinLipoprotein--Associated Associated PhospholipasePhospholipase AA22 (Lp(Lp--PLAPLA22))

•• Hydrolyzes oxidized phospholipids to Hydrolyzes oxidized phospholipids to lysophosphatidylcholinelysophosphatidylcholine and oxidized free fatty acidsand oxidized free fatty acids

•• Unique Unique phospholipasephospholipase distinct from sPLAdistinct from sPLA22; also ; also known as plateletknown as platelet--activating factor activating factor acetylhydrolaseacetylhydrolase

•• CoCo--traffics in circulation with LDL traffics in circulation with LDL •• In WOSCOPS, relative risk for a coronary event was In WOSCOPS, relative risk for a coronary event was

approximately twice as high in the highest quintile of approximately twice as high in the highest quintile of LpLp--PLAPLA22 compared with the lowest quintilecompared with the lowest quintile11

11 Packard CJ et al. Packard CJ et al. N N EnglEngl J MedJ Med 2000;343:11482000;343:1148––1155.1155.

LUMEN

MEDIA

INTIMA

LDLLDL

The Role of Lp-PLA2 in CHD

Lp-PLA2

Adhesion Molecules

LUMEN

MEDIA

INTIMA

Lp-PLA2


Oxidized LDL

Cytokines

Lyso-PC+

OxFA

LDLLDL

LUMEN

MEDIA

INTIMA Lyso-PC+

OxFA

Lp-PLA2

Adhesion Molecules

CytokinesPlaque Formation

Foam Cell

Monocytes

Macrophage


Oxidized LDL

LDLLDL

Ischemic Stroke Hazard Ratios (95% CI) Ischemic Stroke Hazard Ratios (95% CI) by CRP Categories Defined by AHA/CDCby CRP Categories Defined by AHA/CDC

1.97 1.97 (1.14 (1.14 –– 3.393.39))1.54 1.54 (0.91 (0.91 –– 2.622.62))Model 3Model 3§§

1.87 1.87 (1.13 (1.13 –– 3.103.10))1.41 1.41 (0.85 (0.85 –– 2.352.35))Model 2Model 2‡‡

2.70 2.70 (1.69 (1.69 –– 4.314.31))1.651.65 (1.02 (1.02 –– 2.672.67))Model 1Model 1††

High RiskHigh Risk(> 3.0 mg/L)(> 3.0 mg/L)

Average RiskAverage Risk(1.0 (1.0 –– 3.0 mg/L3.0 mg/L))

Categories of Categories of hshs--CRPCRP**

** Low risk (<1 mg/L) is reference; ARIC Low risk (<1 mg/L) is reference; ARIC tertilestertiles were <1.01, 1.01were <1.01, 1.01––2.82, 2.82, and >2.82.and >2.82.

†† Adjusted for age, sex, and raceAdjusted for age, sex, and race‡‡ Also adjusted for smoking status, SBP, LDLAlso adjusted for smoking status, SBP, LDL--C, HDLC, HDL--C, and diabetesC, and diabetes§§ Also adjusted for antihypertensive medication and BMIAlso adjusted for antihypertensive medication and BMI

Ballantyne CM et al. Ballantyne CM et al. Arch Intern MedArch Intern Med 2005;165:24792005;165:2479--2484.2484.

Ischemic Stroke Hazard Ratios (95% CI) Ischemic Stroke Hazard Ratios (95% CI) by Lpby Lp--PLAPLA22 TertilesTertiles

1.971.97 (1.16 (1.16 –– 3.333.33))0.860.86 (0.51 (0.51 –– 1.451.45))Model 3Model 3§§

TertilesTertiles of Lpof Lp--PLAPLA22**

1.931.93 (1.14 (1.14 –– 3.273.27))0.890.89 (0.52 (0.52 –– 1.521.52))Model 4Model 4¶¶

1.911.91 (1.15 (1.15 –– 3.183.18))0.870.87 (0.52 (0.52 –– 1.461.46))Model 2Model 2‡‡2.232.23 (1.48 (1.48 –– 3.343.34))0.870.87 (0.55 (0.55 –– 1.371.37))Model 1Model 1††

33((≥≥ 422 422 µµg/Lg/L))

22(310(310––422422 µµg/Lg/L))

* * Lowest (1st) Lowest (1st) tertiletertile (< 310 (< 310 µµg/Lg/L) is reference) is reference†† Adjusted for age, sex, and raceAdjusted for age, sex, and race‡‡ Also adjusted for smoking status, SBP, LDLAlso adjusted for smoking status, SBP, LDL--C, HDLC, HDL--C, and diabetesC, and diabetes§§ Also adjusted for CRPAlso adjusted for CRP¶¶ Also adjusted for antihypertensive medication and BMIAlso adjusted for antihypertensive medication and BMI


11.38

6.02 5.52

5.844.03

1.000.002.004.006.008.00

10.0012.00

High Medium Low

LowMedium

High

5.525.52

CRP, mg/LCRP, mg/L LpLp--PLAPLA 22, ,

µµg/Lg/L

Isch

emic

Str

oke

Haz

ard

Rat

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chem

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95% CI 3.1395% CI 3.13––41.41,41.41,p<0.001p<0.001

(>3(>3)) (1(1––33)) (<1(<1))

((≥≥422)422)

(310(310––422422))(<310(<310))

6.026.02

2.854.27

Association of LpAssociation of Lp--PLAPLA22 and CRP with and CRP with Incident Ischemic StrokeIncident Ischemic Stroke

4.36


•• Improve global risk assessment, Improve global risk assessment, particularly in intermediateparticularly in intermediate--risk risk patientspatients




AUCsAUCs for Incident CHD in 5 Years: ARICfor Incident CHD in 5 Years: ARIC

6336338048040.006 0.006 §§0.7800.7800.7740.774LpLp--PLAPLA2 2 ‡‡

6666668458450.0030.0030.7700.7700.7670.767Log CRP Log CRP ‡‡

CHD CHD casescasesCRSCRSIncrementIncrement

Basic and Basic and factor factor ††Basic Basic **

Novel risk Novel risk factorfactor

CaseCase––cohort cohort subjects, nsubjects, nAUC at 5 yearsAUC at 5 years

*Basic model included age (continuous), race (white, African American), sex, total cholesterol (continuous), HDL-C (continuous), SBP (continuous), antihypertensive medications (yes or no), smoking status (current smoker or nonsmoker), and diabetes (yes or no)†Basic model plus the indicated novel risk factor‡Sample group 4: visit 2 baseline followed up through 31 December 1998; median follow-up 7.3 years§P < .05 for increase in AUCFolsom A et al. Folsom A et al. Arch Intern MedArch Intern Med 2006;166:13682006;166:1368––1373.1373.

Lloyd-Jones DM et al. Ann Intern Med 2006;145:35-42.

Comparison of Areas under Receiver-Operating Characteristic Curve for Models with Traditional

CVD Risk Factors Alone or with CRP Added

0.72 0.72 ****0.73 0.73 ¶¶NANAmen and men and womenwomen

prospectiveprospectiveCHSCHS

0.800.800.80 0.80 ||||1.61.6men and men and womenwomen

prospectiveprospectiveFramingham Framingham HeartHeart

0.740.740.74 0.74 §1.91.9men and men and womenwomen

prospectiveprospectiveFramingham Framingham OffspringOffspring

0.650.650.64 0.64 ‡1.41.4men and men and womenwomen

nested casenested case––controlcontrol

ReykjavikReykjavik

0.7500.7500.735 0.735 †2.22.2menmenprospectiveprospectiveMONICA MONICA AugsburgAugsburg

0.7480.7480.746 0.746 †1.21.2men and men and womenwomen

nested casenested case––controlcontrol

RotterdamRotterdam0.810.810.81 0.81 *2.32.3womenwomenprospectiveprospectiveWHSWHS

AUC AUC with with CRP CRP addedadded

AUC for AUC for traditional traditional risk factors risk factors

alonealone

MultivariateMultivariate--adjusted RR for adjusted RR for CRP, quartile 4 CRP, quartile 4

vsvs quartile 1quartile 1SexSexDesignDesignStudyStudy

*Age, smoking, DM, BP, HRT, treatment. †Framingham risk score. ‡Age, sex, exam period, TC, smoking, SBP. §Age, sex, metabolic syndrome. ||Age, sex, SBP, TC/HDL||Age, sex, SBP, TC/HDL--C, DM, smoking. C, DM, smoking. ¶¶Age, sex, race, education, CVD, Age, sex, race, education, CVD, elevated SBP, DM, smoking low HDLelevated SBP, DM, smoking low HDL--C, high LDLC, high LDL--C, TG, alcohol, obesity, physical activity, LVH, diuretic use. C, TG, alcohol, obesity, physical activity, LVH, diuretic use. **CRP + 5 other novel risk factors.**CRP + 5 other novel risk factors.

AUCs for Incident Stroke: ARIC

* Age, sex, race, smoking, SBP, LDL-C, HDL-C, diabetes, antihypertensive medication, BMI

< .05< .050.793TRFTRF** + CRP + Lp+ CRP + Lp--PLAPLA22 + + interactioninteraction

< .05< .050.778TRFTRF** + CRP + Lp+ CRP + Lp--PLAPLA22

< .05< .050.759TRFTRF** + CRP+ CRP< .05< .050.747TRFTRF**

P (bootstrap test)P (bootstrap test)AUCAUCModelModel

Nambi V et al. Stroke 2009;40:376–381.

Reclassification of Stroke Risk by Addition of Lp-PLA2 and CRP to Traditional Risk Factors: ARIC

0.011—0.0733.30.03011.00.00685.7Overall

0.0803.10.10165.70.04131.40.0152.9High (>5%)

0.03111.20.05911.10.03363.70.01525.2Moderate (2–5%)

0.00685.7—0.00.0253.40.00596.6Low (<2%)

5-yr risk

% of population

5-yr risk

% of TRF

5-yr risk

% of TRF

5-yr risk

% of TRF

High(>5%)

Moderate(2–5%)

Low(<2%) Overall

Stroke Risk by TRF + CRP + Lp-PLA2

Stroke Risk by TRF

TRF = traditional risk factors: age, sex, race, smoking, SBP, LDL-C, HDL-C, diabetes, antihypertensive medication, BMI


• In analyses of 5-year stroke risk in the ARIC study, the area under the receiver operating characteristic curve was significantly improved by the addition of CRP and Lp-PLA2 to traditional risk factors

• Most reclassification occurred in individuals who were at moderate risk for stroke based on traditional risk factors: only 4% of low-risk individuals but 36% of moderate-risk individuals were reclassified with the addition of CRP and Lp-PLA2 to traditional risk factors

Reclassification of Stroke Risk by Addition of Lp-PLA2 and CRP to Traditional Risk Factors: ARIC


Development and Validation of Two Improved Development and Validation of Two Improved Algorithms for the Assessment of Global Algorithms for the Assessment of Global

Cardiovascular RiskCardiovascular Risk

Derivation Cohort

Validation CohortN = 16,400504 events

N = 8,158262 events

Ridker et al, JAMA 2007;297:611-9

Candidate variables considered in predictive model development. (Transformations and interactions of

these were also considered)Demographic variables

• Age (years)• History of diabetes (yes/no)• Systolic blood pressure (mmHg)• Diastolic blood pressure (mmHg)• Treatment for hypertension (yes/no)• Current smoking (yes/no)• Past smoking (yes/no)• Menopause (yes/no)• Post-menopausal hormone use (yes/no)• Body mass index (kg/m2)• Weight (pounds)• Height (inches)• Race (White, Black, Hispanic, Asian, Pacific

Islander, American Indian/Alaskan Native, Other) • Alcohol use (>once/wk)• Exercise frequency (>once/wk)• Parental history of myocardial infarction before

age 60 years (yes/no)• Current multivitamin use (yes/no)• Migraine (yes/no)• Aspirin use (randomization variable)• Vitamin E (randomization variable)• Beta-carotene (randomization variable)

Blood Biomarkers

• Total cholesterol (yes/no)• High-density lipoprotein cholesterol

(mg/dL)• Low-density lipoprotein cholesterol

(mg/dL)• Non-HDL cholesterol (mg/dL)• Treatment for hyperlipidemia

(yes/no)• Apolipoprotein A-I mg/dL)• Apolipoprotein B100 (mg/dL)• C-reactive protein (mg/L)• Creatinine (mg/dL)• Homocysteine (umol/L)• Lipoprotein(a) (mg/dL)• Hemoglobin A1C• Fibrinogen (mg/dL)• Soluble intercellular adhesion

molecule type-1 (sICAM-1) (ng/mL)


Best FittingModel AAgeHbA1c %) if diabeticLn(SBP)Current SmokingLn(hsCRP)Parental history of MI < age 60

Apo-B100Apo A-I

[Lp(a)-10] if Apo-B100 ≥ 100

Clinically Simplified Model B (Reynolds Risk Score)

AgeHbA1c %) if diabeticLn(SBP)Current SmokingLn(hsCRP)Parental history of MI < age 60

Non-HDL-C (TC-HDL-C)HDL-C

--

Not in the final model:Obesity, exercise levels, alcohol use, creatinine, homocysteine,

fibrinogen, sICAM-1

Risk Reclassification: ATPRisk Reclassification: ATP--III III vsvs Reynolds Risk ScoreReynolds Risk Score


10-Y

ear R

isk

Rey

nold

s R

isk

Scor

e (%

)

0

10

20

30

40

0 10 20 3010-Year Risk ATP-III (%)

405

5

21%

27%

4%

25%

20%

16% 4%

2%75%

55%

56%96%

50 percent of those atintermediate risk according to

ATP-III were reclassifiedby the addition of hsCRP

and family historyto clinically relevant

higher or lower risk groups.

When comparing predicted toobserved event rates,

reclassification was correctin more than 98 percent of cases

4%• all the above were optimal

The Reynolds Risk ScoreCalculating Heart and Stroke

Risk for Women

www.ReynoldsRiskScore.org

JAMA 2007;297:611-619

http://www.ReynoldsRiskScore.org

66 year old nondiabetic Hispanic woman with history of borderline hypertension, not on meds

Height 5'6"Waist 36"Weight 188 lbBMI 30.3BP 145/83hsCRP 3.3

Myocardial infarction age 72

CaseCase

JAMA 2007;297:611-619

Smoker NoTC 231TG 240HDL 57LDL 126Parental history Yes

10-year risk:Framingham Risk Score: 5%Reynolds Risk Score: 10%


•• Guide selection or intensity of Guide selection or intensity of therapytherapy

•• Provide target of therapy if risk factor Provide target of therapy if risk factor and not just markerand not just marker


LpLp--PLAPLA22 and CRP: Markers or and CRP: Markers or Targets of Therapy?Targets of Therapy?

•• LDLLDL--C levels have no correlation to incident C levels have no correlation to incident stroke in ARIC, HPSstroke in ARIC, HPS

•• LDLLDL--C and HDLC and HDL--C levels are strongly correlated C levels are strongly correlated to incident CHDto incident CHD

•• Statins, which reduce LDLStatins, which reduce LDL--C, LpC, Lp--PLAPLA22, and , and CRP, reduce CHD and strokeCRP, reduce CHD and stroke

•• If reductions in LpIf reductions in Lp--PLAPLA22 and CRP are related to and CRP are related to stroke reduction, Lpstroke reduction, Lp--PLAPLA22 and/or CRP may be and/or CRP may be markers for risk and possible targets for therapymarkers for risk and possible targets for therapy

Justification for the Use of statins in Justification for the Use of statins in Primary prevention: an Intervention Trial Primary prevention: an Intervention Trial

Evaluating Rosuvastatin (JUPITER)Evaluating Rosuvastatin (JUPITER)

•• ~15,000 men (age ~15,000 men (age ≥≥55) and women (age 55) and women (age ≥≥65) without 65) without prior cardiovascular event or CHD risk equivalentprior cardiovascular event or CHD risk equivalent

•• CRP CRP ≥≥2 mg/L2 mg/L•• LDLLDL--C <130 mg/C <130 mg/dLdL•• Randomization to rosuvastatin 20 mg/d or placeboRandomization to rosuvastatin 20 mg/d or placebo•• Planned followPlanned follow--up: 3up: 3––4 years4 years•• Primary endpoint:Primary endpoint: first occurrence of a major first occurrence of a major

cardiovascular event (cardiovascular death, stroke, cardiovascular event (cardiovascular death, stroke, myocardial infarction, arterial revascularization, or myocardial infarction, arterial revascularization, or hospitalization for unstable angina)hospitalization for unstable angina)

RidkerRidker PM. PM. CirculationCirculation 2003;108:22922003;108:2292––2292297.7.

0

1

2

3

4

5

hsC

RP

(mg/

L)

0

20

40

60

80

100

120

140

LDL

(mg/

dL)

Months0 12 24 36 48

0

10

20

30

40

50

60

0

20

40

60

80

100

120

140

0 12 24 36 48

TG (

mg/

dL)

HD

L (m

g/dL

)

Months

LDL decrease 50 percent at 12 months

hsCRP decrease 37 percent at 12 months

HDL increase 4 percent at 12 months

TG decrease 17 percent at 12 months

Ridker PM et al. N Engl J Med. 2008;359:2195-2207.

JUPITER: Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP

Placebo 251 / 8901

Rosuvastatin 142 / 8901

HR 0.56, 95% CI 0.46-0.69P < 0.00001

- 44 %

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Follow-up (years)Number at RiskRosuvastatinPlacebo

8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174

JUPITER: Primary Endpoint (MI, Stroke, UA/Revascularization, CV Death)

Ridker PM et al. N Engl J Med. 2008;359:2195-2207.

02

46

810

24

68

Rec

urre

nt M

yoca

rdia

l Inf

arct

ion

or D

eath

(per

cent

)

PROVE IT – TIMI 22NEJM 2005;352:20-28.

0

2

4

6

8

10

0 120 240 360 480 600Follow-up (days)

A to ZCirculation 2006;114:281-8

Clinical Relevance of Achieving LDL-C < 70 mg/dL and hsCRP < 2 mg/LFollowing Initiation of Statin Therapy

0 180 360 540 720 900

Follow-up (days)

LDL>70, hsCRP>2 LDL<70, hsCRP>2 LDL>70, hsCRP<2 LDL<70, hsCRP<2

JUPITER Dual Target Analysis: LDLC<70 mg/dL, hsCRP<2 mg/L

LDL > 70 mg/dLand / or

hsCRP > 2 mg/LHR 0.64 (0.49-0.84)

LDL < 70 mg/dLand

hsCRP < 2 mg/L HR 0.35 (0.23-0.54)

Placebo HR 1.0 (referent)

P < 0.0001

0 1 2 3 4

0.00

0.02

0.04

0.06

0.08

Cum

ulat

ive

Inci

denc

e

Number at Risk Follow-up (years)

RosuvastatinPlacebo

7,716 7,699 7,678 6,040 3,608 1,812 1,254 913 508 1457,832 7,806 7,777 6,114 3,656 1,863 1,263 905 507 168

Jupiter: LimitationsJupiter: Limitations

1.1. No control group to test the hypothesis that No control group to test the hypothesis that low LDLlow LDL--C and low C and low hsCRPhsCRP do not have do not have benefit from benefit from statinsstatins, no published studies , no published studies have shown significant treatment interaction have shown significant treatment interaction between between statinsstatins and and hsCRPhsCRP

2.2. Impossible to answer the question of Impossible to answer the question of whether CRP levels are a target of therapy whether CRP levels are a target of therapy (dual targets) based upon Jupiter as not (dual targets) based upon Jupiter as not designed to answer this questiondesigned to answer this question

-2

0

2

Plaque CompositionPlaque Compositionby IVUS by IVUS -- VHVH

change from baseline in necrotic core volumechange from baseline in necrotic core volume

-2

5

entire region of interest [mean 48 mm]key secondary endpoint

mean

chan

ge (m

m3 )

p=0.012

* p=0.009

p=0.71

7

the worst 10 mm subsegment

mean

chan

ge (m

m3 )

p=0.003

p=0.162

* p=0.008

placebo (plus standard of care) n=110 darapladib 160 mg (plus standard of care) n=129

Between groups comparison: ANCOVA adjusted for ACS, pooled country, baseline value and segment length; within groups comparison: paired t test

Serruys PW et al. Circulation 2008;118:1172–1182.

Selective LpSelective Lp--PLA2 Inhibitor PLA2 Inhibitor DarapladibDarapladib

STABILITY:STABILITY:Aim of StudyAim of Study

•• To evaluate clinical efficacy of longTo evaluate clinical efficacy of long--term treatment with term treatment with darapladibdarapladib (Lp(Lp--PLAPLA22 inhibitor) versus placebo when inhibitor) versus placebo when added to standard of care in chronic added to standard of care in chronic CHD patient population on the CHD patient population on the incidence of major cardiovascular incidence of major cardiovascular eventsevents

ConclusionsConclusions

1.1. Inflammatory biomarkers such as Inflammatory biomarkers such as hshs--CRP CRP and Lpand Lp--PLAPLA22, improve risk classification in , improve risk classification in intermediateintermediate--risk individualsrisk individuals

2.2. Data do not support use in the entire adult Data do not support use in the entire adult populationpopulation

3.3. No current biomarkers have been validated No current biomarkers have been validated to examine "to examine "antiatheroscleroticantiatherosclerotic" efficacy of " efficacy of therapytherapy

4.4. Individuals with high Individuals with high hshs--CRP levels benefit CRP levels benefit from from statinstatin therapy even if LDLtherapy even if LDL--C is not C is not elevatedelevated

ConclusionsConclusions

1.1. Patients who are on Patients who are on statinstatin therapy with high therapy with high levels of levels of hsCRPhsCRP have higher events than have higher events than those with low levels of those with low levels of hsCRPhsCRP but no data but no data on how such patients should be treated to on how such patients should be treated to improve outcomesimprove outcomes

2.2. Ongoing trials will examine if targeting Ongoing trials will examine if targeting LpPLA2 reduces CV events in high risk LpPLA2 reduces CV events in high risk patientspatients

Limitations with Current ApproachesLimitations with Current Approaches

•• "Candidate molecule""Candidate molecule"——biology based biology based related to inflammation and thrombosis, related to inflammation and thrombosis, neither of which is specific to neither of which is specific to atherosclerosisatherosclerosis

•• Therefore, problems with specificity, Therefore, problems with specificity, sensitivity, very small increases in AUC of sensitivity, very small increases in AUC of ROC, modest net reclassification indexROC, modest net reclassification index

•• Approach may still more useful for Approach may still more useful for identifying targets of therapy, i.e., "risk identifying targets of therapy, i.e., "risk factors"factors"

Future Directions to Develop More Future Directions to Develop More Specific and More Sensitive BiomarkersSpecific and More Sensitive Biomarkers

•• GenomicsGenomics–– Gene expression and profiling in Gene expression and profiling in

cells/lesionscells/lesions–– Genetic polymorphisms associated with Genetic polymorphisms associated with

CHD from GWASCHD from GWAS•• ProteomicsProteomics

–– Profile of differential expression of Profile of differential expression of proteins in cell/lesionsproteins in cell/lesions

–– MicrosequencingMicrosequencing by mass spectrometryby mass spectrometry

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