aha 2005 crp cost effectiveness
TRANSCRIPT
Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP Screening
1. Adjunct to Global Risk Assessment1. Adjunct to Global Risk Assessment2. Method to Monitor Statin Efficacy in Secondary Prevention2. Method to Monitor Statin Efficacy in Secondary Prevention
3. Method to Target Statin Therapy in Primary Prevention3. Method to Target Statin Therapy in Primary Prevention
Paul M Ridker, MDPaul M Ridker, MDEugene Braunwald Professor of MedicineEugene Braunwald Professor of Medicine
Harvard Medical SchoolHarvard Medical SchoolDirector, Center for Cardiovascular Disease PreventionDirector, Center for Cardiovascular Disease Prevention
Brigham and Women’s HospitalBrigham and Women’s HospitalBoston, MassachusettsBoston, Massachusetts
Dr Ridker is listed as a co-inventor on patents held by the Brigham and Women’s Hospitalthat relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes.
Pasceri and Yeh, Circulation 100:2124-2126, 1999
Circulation
Primary Pro-Inflammatory Primary Pro-Inflammatory Cytokines Cytokines
( e.g., IL-1, TNF-( e.g., IL-1, TNF-)) IL-6IL-6““Messenger” Messenger” CytokineCytokineICAM-1ICAM-1
Selectins, HSPs, Selectins, HSPs, etc.etc.
LiverLiverEndotheliumEndotheliumand other cellsand other cells
Circulation 1999;100:1148–1150.
Pro-Inflammatory PathwaysPro-Inflammatory Pathways
Pro-Inflammatory Risk Pro-Inflammatory Risk FactorsFactors
CRPCRPSAASAA
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*
Fra
min
gham
Ad j
u ste
d R
e la t
ive
Ri s
khsCRPhsCRP Adds Prognostic Information Beyond the Adds Prognostic Information Beyond the
Framingham Risk Score in ALL Major Cohorts EvaluatedFramingham Risk 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
1
2
3
4
Low Medium High
Fully
Adj
uste
d R
elat
ive
Ris
k
0
1
2
3
4
Low Medium High
TC : HDLC Ratio Apo B100 : Apo A-I Ratio
hsCRP < 1 mg/L hsCRP 1 to 3 mg/L hsCRP > 3 mg/L
JAMA 2005;294:326-333
Additive Value of hsCRP Across All Lipid RatiosRisks Adjusted for Age, Blood Pressure, Smoking Status, Body Mass Index, and Diabetes
0.0
5.0
10.0
15.0
20.0
25.0
30.0
10-20 5-10 <5 <0.50.5-1.0
1.0-3.03.0-10.0
>10.0
Moving Toward an hs-CRP Modified Moving Toward an hs-CRP Modified Framingham Risk ScoreFramingham Risk Score
Calculated Framingham 10-Year RiskCalculated Framingham 10-Year Risk
Ridker PM, Wilson PW, Grundy S. Circulation 2004;109:2818-2925
hs-CRP mg/Lhs-CRP mg/LC
RP
Mod
ified
Fra
min
gham
Ris
kC
RP
Mod
ified
Fra
min
gham
Ris
k
hsCRP Enters Global Risk Prediction Models hsCRP Enters Global Risk Prediction Models Before Before TC, TC, HDL, and LDLCHDL, and LDLC
Variable LR Chi -Square
Model with age plus:
SBP 100.60
Ln(CRP) 86.72
Current smoking 74.04
Ln(HDL) 70.19
Ln(Total Cholesterol) 36.72
LDL 31.13
Variable LR Chi - Square
Model with age, SBP, smoking plus:
Ln(CRP) 44.05
Ln(HDL) 41.89
Ln(Total Cholesterol) 26.28
LDL 22.94
N Cook 2005
Comparison of model fit for ATP III risk prediction with and Comparison of model fit for ATP III risk prediction with and without CRPwithout CRP
ATP Prediction Model Without CRP With
CRP
Liklihood ratio Chi-squareBayes Information Criteria (BIC)BIC weight (posterior probability)Akaike Information Criteria (AIC)AIC weightsNagelkerke’s Generalized R2
C-statisticAdjusted C-statisticD-statisticAdjusted D-statisticBrier Score
Regardless of Measure Used, the Addition of hsCRP Improves Predictive Modeling
0-<5% 5-<10% 10-<20% 20%+
5-<10% 2.4% 7.8% 15.2% - 10-<20% - 6.8% 11.5% 19.8%
20%+ - - 18.8% 27.1%
Global Risk With CRP (10 year risk)Global RiskWithout CRP(10 year risk)
ProportionCorrectly
Reclassified
21.3 %
20.0 %
13.9 %
Additive Value of hsCRP to Global Risk Prediction Models – Additive Value of hsCRP to Global Risk Prediction Models – Observed Risk and Proportion Correctly ReclassifiedObserved Risk and Proportion Correctly Reclassified
32.4%
42.2 %
19.4 %
WHS ATP-III
Between 20 and 40 percent of all individuals with 5 to 20 percent risk by ATP-IIIare reclassified more accurately and with greater precision by adding hsCRP; these
proportions are significantly LARGER than those associated with LDL, HDL, or TG screening
Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP ScreeningPart 1. Adjunct for Global Risk Assessment: Part 1. Adjunct for Global Risk Assessment:
Comparison to TC, LDL, or HDLComparison to TC, LDL, or HDL
Since the predictive value of hsCRP is equal to or superior to that of TC, LDL-C, or HDLC;
and since the cost of hsCRP is less than or equalto that of lipid screening
then hsCRP screening must be at least as cost effective for broad population screening
as is lipid evaluation.
The Clinical Issue : hsCRP Reduction and Patient The Clinical Issue : hsCRP Reduction and Patient ManagementManagement
There is no hard evidence to date that lowering There is no hard evidence to date that lowering hsCRP hsCRP per seper se will reduce vascular risk. will reduce vascular risk.
However, However, allall observational evidence indicates that observational evidence indicates that those with lower hsCRP levels after treatment have those with lower hsCRP levels after treatment have better short and long term prognosis.better short and long term prognosis.
Clinical Predictive Value of Very Low as Well Clinical Predictive Value of Very Low as Well as Very High Levels of hsCRPas Very High Levels of hsCRP
0
1
2
3
4
5
6
7
8
<0.5 0.5-1.0 1.0-2.0 2.0-3.0 3.0-4.0 4.0-5.0 5.0-10.0 10.0-20.0 >20
hsCRP (mg/L)
Rela
tive
Risk
of F
utur
e CV
Eve
nts
“low risk” “moderate risk” “high risk”
Circulation 2004;109:1955-59
Follow-Up (years)0.0 0.5 1.0 1.5 2.0 2.5
0.00
0.02
0.04
0.06
0.08
0.10
CRP>2 mg/L
CRP<2 mg/L
0.0 0.5 1.0 1.5 2.0 2.5
0.00
0.02
0.04
0.06
0.08
0.10
C
umul
ativ
e R
ate
of
Rec
urre
nt M
yoca
rdia
l Inf
arct
ion
or C
oron
ary
Dea
th (p
erce
nt)
LDLC>70 mg/dL
LDLC<70 mg/dL
Clinical Relevance of Achieved LDL and Achieved CRP
After Treatment with Statin Therapy
NEJM 2005;352:20-28.
0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5
0.00
0.02
0.04
0.06
0.08
0.10
0.02
0.04
0.06
0.08
0.10
Rec
urre
nt M
yoca
rdia
l Inf
arct
ion
or C
oron
ary
Dea
th (p
erce
nt)
Follow-Up (Years)
LDL > 70 mg/dL, CRP > 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP < 2 mg/L
Clinical Relevance of Achieved LDL and Achieved CRP
After Treatment with Statin Therapy
NEJM 2005;352:20-28.
0.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.50.0 0.5 1.0 1.5 2.0 2.5
0.00
0.02
0.04
0.06
0.08
0.10
0.02
0.04
0.06
0.08
0.10
Rec
urre
nt M
yoca
rdia
l Inf
arct
ion
or C
oron
ary
Dea
th (p
erce
nt)
Follow-Up (Years)
LDL > 70 mg/dL, CRP > 2 mg/L
LDL < 70 mg/dL, CRP > 2 mg/LLDL > 70 mg/dL, CRP < 2 mg/L
LDL < 70 mg/dL, CRP < 2 mg/L
Clinical Relevance of Achieved LDL and Achieved CRP
After Treatment with Statin Therapy
LDL < 70 mg/dL, CRP < 1 mg/L
NEJM 2005;352:20-28.
Nissen et al NEJM 2005; 352:29-38
Effects of LDL Reduction and CRP Reduction on AtheroscleroticProgression Measured By Intravascular Ultrasound : REVERSAL
REVERSAL: Regression of Atherosclerosis On REVERSAL: Regression of Atherosclerosis On Statin Therapy Only Occurs Among Those with Statin Therapy Only Occurs Among Those with
CRP ReductionCRP Reduction
-4
-2
0
2
4
6
8
10
Cha n
g e i n
Ath
e ro m
a Vo
lum
e (m
m3 )
Nissen et al NEJM 2005; 352:29-38
LDLCRP
LDLCRP
LDLCRP
LDLCRP
Progression
Regression
+8mm3
+2mm3
- 1mm3
- 2mm3
Importance of Achieving Low LDLC and Low hsCRP After Initiation Importance of Achieving Low LDLC and Low hsCRP After Initiation of Statin Therapy : Carotid IMT Regression in ARBITERof Statin Therapy : Carotid IMT Regression in ARBITER
01020304050607080
Kent SM, Taylor AJ. AJC 2003;92:1224-1227
LDL > 130
LDL 100 - 129
LDL70 - 99
LDL< 70
LDL< 70
hsCRP> 2
LDL< 70
hsCRP < 2
Prop
o rti
on w
ith
I MT
Regr
ess i
on
Cost-Effectiveness of hsCRP ScreeningCost-Effectiveness of hsCRP ScreeningPart 2. High Risk Secondary Prevention to Monitor Part 2. High Risk Secondary Prevention to Monitor
Statin EfficacyStatin Efficacy
1.1. Patients on statin therapy who achieve low hsCRP levels have Patients on statin therapy who achieve low hsCRP levels have better clinical outcomes at all levels of achieved LDL-C.better clinical outcomes at all levels of achieved LDL-C.
2.2. The best clinical outcomes are obtained among statin treated The best clinical outcomes are obtained among statin treated patients who achieve the patients who achieve the “dual goals”“dual goals” of LDL-C < 70 mg/dL of LDL-C < 70 mg/dL andand hsCRP < 2 mg/L.hsCRP < 2 mg/L.
3.3. The relationship between achieved LDL-C and achieved hsCRP The relationship between achieved LDL-C and achieved hsCRP is highly variable for individual patients and cannot be predicted is highly variable for individual patients and cannot be predicted on the basis of intensity of therapy. on the basis of intensity of therapy.
4.4. Strategies to cost-effectively lower cardiovascular risk with Strategies to cost-effectively lower cardiovascular risk with statins may need to measure and monitor hsCRP in a manner statins may need to measure and monitor hsCRP in a manner analogous to how we currently measure and manage LDL-C.analogous to how we currently measure and manage LDL-C.
CRP as a Method to Target Statin Therapy in Primary CRP as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPSPrevention: AFCAPS/TexCAPS
Study Group Statin Placebo NNT
low LDLC / low CRP 0.025 0.022 ----
low LDLC / high CRP 0.029 0.051 48
high LDLC / low CRP 0.020 0.050 33
high LDLC / high CRP 0.038 0.055 58
Median LDLC = 149 mg/dLMedian CRP = 0.16 mg/dL
N Engl J Med 2001;344:1959-65
No History of CADMen >55, Women > 65 LDL-C <130 mg/dL
CRP >2 mg/L
Rosuvastatin (N =7500)
Placebo (N =7500)
MIStroke
Unstable Angina
CVD DeathCABG/PTCA
LDLCRPFHS
Lipidshs-CRP LFTs
Lipidshs-CRPHbA1C
JUPITERJUPITERRandomized Trial of Rosuvastatin in the Primary Randomized Trial of Rosuvastatin in the Primary
Prevention of Cardiovascular Events Among Individuals Prevention of Cardiovascular Events Among Individuals with Low Levels of LDL-C and Elevated Levels of CRPwith Low Levels of LDL-C and Elevated Levels of CRP
4 week Run-in
Screening Visit
Randomization Visit
Safety Visit
Bi-Annual Follow-Up Visits
End of Study Visit
Lipidshs-CRP LFTsHbA1C
JUPITER Investigators, Circulation 2003
Estimated Life Expectancy Gains : hsCRPEstimated Life Expectancy Gains : hsCRPPrimary prevention in 35 year old men and womenPrimary prevention in 35 year old men and women
Intervention Gains in Life Expectancy (months)Men Women
Statin Therapy for high CRP / low LDL 10.2 7.9
Eliminate Smoking 10.0 8.0Reduce DBP to 88 mm Hg 13.2 4.8Eliminate CHD 37.2 39.6
Mammography 50 yr old women NA 0.8Pap smear 20 year old women NA 3.1
Blake G, Kuntz K, JACC 2002;40:49-55
Blake G, Kuntz K. Am J Med 2003;114:485-94
“A strategy involving C-reactive protein screening totarget statin therapy among middle-aged patients
without hyperlipidemia is relatively cost-effective and, in some cases, cost-saving”
“Overall, cost-effectiveness ratios were comparableto those reported for primary prevention
using statin therapy among those with hyperlipidemia”
Cost-Effectiveness of hsCRP Screening Cost-Effectiveness of hsCRP Screening Part Part 3.3. : Targeting Statin Therapy for Primary : Targeting Statin Therapy for Primary
PreventionPrevention
Blake G, Kuntz K, Am J Med 2003;114:485-94
Cost-Effectiveness of hsCRP Screening Cost-Effectiveness of hsCRP Screening Part 2 : Part 2 : Targeting Statin TherapyTargeting Statin Therapy
0102030405060708090
100
$500/yr $1000/yr$
/ QAL
Y (0
00)
0-5 5-10 10-15 15-20 20-25Ten-year Risk of Coronary Heart Disease
CostSaving
CostEffective
CostComparable
Atherosclerosis Test
Very Low Risk3
Negative Test• CCS =0• CIMT<50th percentile
LowerRisk
ModerateRisk
Positive Test• CCS ≥1• CIMT 50th percentile or Carotid Plaque
ModeratelyHigh Risk
HighRisk
VeryHigh Risk
No Risk Factors5 + Risk Factors • CCS <100 & <75th% • CIMT <1mm & <75th%
& No Carotid Plaque
• Coronary Calcium Score (CCS)or
• Carotid IMT (CIMT) & Carotid Plaque4
• CCS 100-399 or >75th%• CIMT 1mm or >75th%
or <50% Stenotic Plaque
• CCS >100 & >90th%or CCS 400
• 50% Stenotic Plaque6
IndividualizedIndividualizedIndividualized5-10 years5-10 yearsRe-test Interval
<70 mg/dl<100 mg/dl<70 Optional
<130 mg/dl<100 Optional
<130 mg/dl<160 mg/dlLDLTarget
All >75y receive unconditional treatment2
Apparently Healthy Population Men>45y Women>55y1
ExitExit
Myocardial IschemiaTest
NoAngiography
Follow Existing Guidelines
Yes
The 1st S .H .A .P .E . GuidelineTowards the National Screening for Heart Attack Prevention and Education (SHAPE) Program
Step 1
Step 2
Step 3Optional
CRP>4mg
ABI<0.9
0.0
2.0
4.0
6.0
8.0
High Medium Low <4.0
>4.0
Combined Use of CT Calcium Scores and CRP in the Combined Use of CT Calcium Scores and CRP in the Prediction of Cardiovascular Events: Prediction of Cardiovascular Events:
South Bay Heart WatchSouth Bay Heart Watch
EBCT Calcium ScoreEBCT Calcium Score
Park R, Detrano R, Xiang M, et al. Circulation 2002;106:2073-7
hs-CRP, mg/L
hs-CRP, mg/L
Rel
ativ
e R
isk
Rel
ativ
e R
isk
hsCRP and Progression of Cerebral Small-Vessel hsCRP and Progression of Cerebral Small-Vessel Disease:Disease:
The Rotterdam Scan StudyThe Rotterdam Scan Study
0
0.5
1
1.5
2
2.5
3
3.5
1 2 3 4
Quartile of hsCRP At Study Entry
Adju
sted
Odd
s Rat
io*
Van Dijk et al, Circulation 2005;112:900-905
Periventricular WML Progression
Subcortical WML Progression
*Adjusted for age, sex, diabetes, smoking, BMI, HTN, TC:HDLC, carotid plaques, and IMT
hsCRP and SAA Predict Short-Term Progression ofhsCRP and SAA Predict Short-Term Progression ofAtherosclerosis Lesions in Human Carotid ArteriesAtherosclerosis Lesions in Human Carotid Arteries
Schillinger et al, Circulation 2005;111:2203-9
0
1
2
3
4
1 2 3 4 5
SAAhsCRP
Quintile of hsCRP or SAA at Baseline
Adj u
sted
OR
for
Car o
tid
P rog
res s
ion
Adjusted for age, gender, BMI, HbA1c, smoking, BP, LDL-C, , family history, and IMT
(N = 1268, 7.5 month f/u)
February 23, 2004
1995 – Cholesterol
2005 – Cholesteroland Inflammation
Broad Screening: Blood Pressure
TC, HDLC, glucose, hsCRP, ABI
Targeted Screening: Imaging
Statin Monitoring:
LDLC, hsCRP
“If CRP was half as effectiveand twice as expensive,physician use would be
ten times higher”
Moving Toward New National Screening Guidelines