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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
1
2
< 1 1 - 3 > 30
1
2
< 1 1 - 3 > 3
WHS
0
1
2
< 1 1 - 3 > 30
1
2
< 1 1 - 3 > 3
ARICMONICAPHS
0
1
2
< 1 1 - 3 > 30
1
2
< 1 1 - 3 > 3
HPFSNHS
0
1
2
1 2 3
Reykjavik*
Fram
ingh
am A
djus
ted
Rel
ativ
e R
isk
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
1
2
<1 1-3 >3
CHS
0
1
2
<1 1-3 >3
EPIC-Norfolk
1997 2002 2004 2004 2004
2004 2004 2005 2005
0
1
2
<1 1-3 >3
2005
PIMA
0
5
10
15
20
25
0–1 2–4 5–9 ≥10 130–160
Multiv
aria
ble
Rel
ativ
e R
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
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
The Role of Lp-PLA2 in CHD
Oxidized LDL
Cytokines
Lyso-PC+
OxFA
LDLLDL
LUMEN
MEDIA
INTIMA Lyso-PC+
OxFA
Lp-PLA2
Adhesion Molecules
CytokinesPlaque Formation
Foam Cell
Monocytes
Macrophage
The Role of Lp-PLA2 in CHD
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
Ballantyne CM et al. Ballantyne CM et al. Arch Intern MedArch Intern Med 2005;165:24792005;165:2479--2484.2484.
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
ioIs
chem
ic S
trok
e H
azar
d R
atio
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
Ballantyne CM et al. Ballantyne CM et al. Arch Intern MedArch Intern Med 2005;165:24792005;165:2479--2484.2484.
•• Improve global risk assessment, Improve global risk assessment, particularly in intermediateparticularly in intermediate--risk risk patientspatients
•• 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?
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
Nambi V et al. Stroke 2009;40:376–381.
• 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
Nambi V et al. Stroke 2009;40:376–381.
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)
Ridker et al, JAMA 2007;297:611-9
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
Ridker et al, JAMA 2007;297:611-9
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
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%
•• Improve global risk assessment, Improve global risk assessment, particularly in intermediateparticularly in intermediate--risk patientsrisk patients
•• 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
How Can Biomarkers be Used to How Can Biomarkers be Used to Improve Patient Care?Improve Patient Care?
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.
•• 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?
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