Inflammatory Markers, Pharmacotherapy, and Clinical Trials Paul M. Ridker, M.D., M.P.H., and Christie M. Ballantyne, M.D

Inflammatory Markers,Inflammatory Markers,

Pharmacotherapy, and Clinical TrialsPharmacotherapy, and Clinical Trials

Paul M. Ridker, M.D., M.P.H., and Christie Paul M. Ridker, M.D., M.P.H., and Christie

M. Ballantyne, M.D.M. Ballantyne, M.D.

Is there clinical evidence that Is there clinical evidence that

inflammation can be modified by inflammation can be modified by

preventive therapies?preventive therapies?

0

1

2

3

4

5

hs-CRP, Aspirin, and Risks of Future MI: hs-CRP, Aspirin, and Risks of Future MI: Physicians' Health StudyPhysicians' Health Study

Adapted from Ridker PM et al. N Engl J Med 1997;336:973-979.©1997 Massachusetts Medical Society. All rights reserved.

Quartile of C-Reactive Protein

1 2 3 4

Aspirin

Placebo

Rela

tive R

isk

of

MI

Low-Dose Aspirin Reduces Thromboxane Low-Dose Aspirin Reduces Thromboxane

BB22 but not CRP but not CRP

Seru

m C

RP

(% o

f B

ase

line)

140

120

100

80

60

40

20

0Placebo(n=11)

Feldman M et al. J Am Coll Cardiol 2001;37:2036-2041.

140

120

100

80

60

40

20

0Seru

m T

hro

mb

oxane

(% o

f B

ase

line)

ASA 81 mg qd(n=13)

Placebo(n=11)

ASA 81 mg qd(n=13)

28 Days31 Days

* p<0.001

* *

Reduction of Proinflammatory Cytokines Reduction of Proinflammatory Cytokines and CRP with Higher-Dose Aspirin in and CRP with Higher-Dose Aspirin in Patients with Chronic Stable AnginaPatients with Chronic Stable Angina

Ikonomidis I et al. J Am Coll Cardiol 1999;100:793-798.

Placebo(n=40)

ASA 300 mg(n=40)

P

MCSF, pg/mL 991(459-1476)

843(501-1357)

<0.05

IL-6, pg/mL 3.5(3.2-4.6)

2.9(2.5-3.4)

<0.05

CRP, mg/mL 1.4(0.54-4.05)

1(0.5-3.1)

<0.05

0

5

10

15

20

25

Elevated CRP Levels in Obesity: Elevated CRP Levels in Obesity: NHANES 1988-1994NHANES 1988-1994

Visser M et al. JAMA 1999;282:2131-2135.

Normal

Perc

en

t w

ith C

RP

0.2

2

mg/d

L

Overweight Obese

Effects of Weight Loss on CRPEffects of Weight Loss on CRPConcentrations in Obese Healthy WomenConcentrations in Obese Healthy Women

83 women (mean BMI 33.8, range 28.2-43.8 kg/m2) placed on very low fat, energy-restricted diet (6.0 MJ, 15% fat) for 12 weeks

Baseline CRP positively associated with BMI (r=0.281, p=0.01)

CRP reduced by 26% (p<0.001)

Average weight loss 7.9 kg, associated with change in CRP

Change in CRP correlated with change in TC (r=0.240, p=0.03) but not changes in LDL-C, HDL-C, or glucose

At 12 weeks, CRP concentration highly correlated with TG (r=0.287, p=0.009), but not with other lipids or glucose

Heilbronn LK et al. Arterioscler Thromb Vasc Biol 2001;21:968-970.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

Effects of Weight Loss in Obese Women on Effects of Weight Loss in Obese Women on IL-6, TNF-IL-6, TNF-, and CRP, and CRP

Bastard J-P et al. J Clin Endocrinol Metab 2000;85:3338-3342.

pg/m

L mg

/L

IL-6 TNF- CRP

Before diet

After very low calorie diet (mean BMI reduction 2.1 kg/m2; mean reduction in body fat mass 4 kg)

p=0.05

p=0.6

p=0.14

-50

-40

-30

-20

-10

0

Effects of n-3 Fatty Acid Therapy on Lipids Effects of n-3 Fatty Acid Therapy on Lipids and sCAMsand sCAMs

Perc

en

t C

han

ge

Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731.

TG TC sICAM-1 sE-selectin

All Patients

DM Patients

*

*

**

* p<0.05

Effect of ACE Inhibition vs. Angiotensin II Effect of ACE Inhibition vs. Angiotensin II Receptor Blockade on sCAMs and CRP in Receptor Blockade on sCAMs and CRP in Type 1 Diabetics with Diabetic NephropathyType 1 Diabetics with Diabetic Nephropathy

580

590

600

610

620

630

640

650

660

200

220

240

260

280

300

Andersen S et al. Diabetes Care 2000;23:1031-1032.

PlaceboPlaceboLosartan 50 mgLosartan 50 mg

Losartan 100 mgLosartan 100 mg

Enalapril 10 mgEnalapril 10 mg


*p<0.05 vs. *p<0.05 vs. placeboplacebo

**

** **sVC

AM

-1, ng/m

l sICA

M-1

, ng/m

l

Effect of ACE Inhibition vs. Angiotensin II Effect of ACE Inhibition vs. Angiotensin II Receptor Blockade on sCAMs and CRP in Receptor Blockade on sCAMs and CRP in Type 1 Diabetics with Diabetic NephropathyType 1 Diabetics with Diabetic Nephropathy

50

51

52

53

54

55

56

57

58

59

60

0.50

0.60

0.70

0.80

0.90

1.00

1.10

1.20

PlaceboPlaceboLosartan 50 mgLosartan 50 mg

Losartan 100 mgLosartan 100 mg



*p<0.05 vs. *p<0.05 vs. placeboplacebo

****

sE-s

ele

ctin

, ng/m

lC

RP, n

g/m

l

Andersen S et al. Diabetes Care 2000;23:1031-1032.

Effect of HRT on hs-CRP: Effect of HRT on hs-CRP: the PEPI Studythe PEPI Study

3.0

2.0

1.0hs-

CR

P (

mg/d

L)

Months

0 12 36

Cushman M et al. Circulation 1999;100:717-722.1999 Lippincott Williams & Wilkins.

CEE + MPA cyclicCEE + MPA continuousCEE + MPCEE

Placebo

0.0

0.5

1.0

1.5

2.0

hs-CRP and Relative Risk of Recurrent hs-CRP and Relative Risk of Recurrent Coronary Events: Coronary Events: CARECARE

Ridker PM et al. Circulation 1998;98:839-844.1998 Lippincott Williams & Wilkins.

1<0.12

Rela

tive R

isk

Quintile of hs-CRP (range, mg/dL)

P=0.02

20.12-0.20

30.21-0.37

40.38-0.66

5>0.66

PP Trend = 0.044 Trend = 0.044

0

1

2

3

Inflammation, Pravastatin, and Relative Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: Risk of Recurrent Coronary Events: CARECARE


Pravastatin

Rela

tive R

isk

Inflammation Absent

PP Trend = 0.005 Trend = 0.005

Placebo Pravastatin Placebo

Inflammation Present

Mean B

ase

line (

mg

/dL) Inflammation absent

Inflammation present

250

200

150

100

50

0TC LDL-C HDL-C TG

Baseline Lipid Levels in Patients with and Baseline Lipid Levels in Patients with and without Inflammation: without Inflammation: CARECARE

Ridker PM et al. Circulation 1998;98:839-844.

Long-Term Effect of Pravastatin on hs-CRP:Long-Term Effect of Pravastatin on hs-CRP:CARE Placebo and Pravastatin GroupsCARE Placebo and Pravastatin Groups

Adapted from Ridker PM et al. Circulation 1999;100:230-235.1999 Lippincott Williams & Wilkins.

PravastatinPravastatin

PlaceboPlacebo

Med

ian

hs-

CR

PC

on

cen

trati

on

(m

g/d

L)

––21.6%21.6%((PP=0.007)=0.007)

0.25

0.24

0.23

0.22

0.21

0.20

0.19

0.18Baseline 5 Years

Change in hs-CRP Concentration Over 5 Change in hs-CRP Concentration Over 5 Years: Years: CARE Subgroup AnalysesCARE Subgroup Analyses

Change in hs-CRP over 5 Years (mg/dL)

HDL-C <35 mg/dL

All Subjects

Pravastatin

Age >60 yearsAge <60 yearsBMI >27 kg/m2

BMI <27 kg/m2

Placebo

SmokersNonsmokers

SBP >128 mm HgSBP <128 mm HgDBP >78 mm HgDBP <78 mm Hg

LDL-C >138 mg/dLLDL-C <138 mg/dLHDL-C >35 mg/dL

Triglycerides >160 mg/dLTriglycerides <160 mg/dL

-0.2 -0.1 0 0.1 0.2 0.3

Ridker PM et al. Circulation 1999;100:230-235.

Change in hs-CRP according to Observed Changes Change in hs-CRP according to Observed Changes in LDL-C: in LDL-C: CARE Placebo and Pravastatin GroupsCARE Placebo and Pravastatin Groups

Change in LDL-C (mg/dL)

Increase0–25

Decrease0–25

Decrease25–50

Decrease50–75

Decrease>75

Change in h

s-C

RP

(mg/d

L)

Placebo

Pravastatin

-0.15

-0.10

-0.05

0

0.05

0.10

0.15


Relative Risks of Future MI among Apparently Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Healthy Middle-Aged Men: Physician’s Health StudyPhysician’s Health Study

Relative Risk for Future MI0 1.0 2.0 4.0 6.0

Lipoprotein(a)Homocysteine

FibrinogentPA Antigen

hs-CRPhs-CRP + TC/HDL-C

Total Cholesterol

TC:HDL-C

Ridker PM. Ann Intern Med 1999;130:933-937.1999 ACP-ASIM.

CRP in Combination with LDL-C as a Method CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary to Target Statin Therapy in Primary Prevention: Prevention: AFCAPS/TexCAPSAFCAPS/TexCAPS

Ridker PM et al. N Engl J Med 2001;344:1959-1965.

Study Group Lovastatin Placebo NNT

Low LDL-C/low CRP 0.025 0.022 _

Low LDL-C/high CRP 0.029 0.051 48

High LDL-C/low CRP 0.020 0.050 33

High LDL-C/high CRP 0.038 0.055 58

Median LDL-C = 149.1 mg/dLMedian CRP = 0.16 mg/dL

Event Rate

CRP in Combination with TC:HDL-C Ratio as CRP in Combination with TC:HDL-C Ratio as a Method to Target Statin Therapy in a Method to Target Statin Therapy in Primary Prevention: Primary Prevention: AFCAPS/TexCAPSAFCAPS/TexCAPS

Ridker PM et al. N Engl J Med 2001;344:1959-1965.

Study Group Lovastatin Placebo NNT

Low TC:HDL-C/low CRP 0.024 0.025 983

Low TC:HDL-C/high CRP 0.025 0.050 43

High TC:HDL-C/low CRP 0.021 0.050 35

High TC:HDL-C/high CRP 0.041 0.057 62

Median TC:HDL-C = 5.96Median CRP = 0.16 mg/dL

Event Rate

hs-CRP: Potential Clinical Applicationshs-CRP: Potential Clinical Applications

Adjunct to lipid screening in the detection of individuals at high risk for coronary artery disease

Method to better target statin therapy in the setting of primary prevention

Potential prognostic value in acute coronary syndromes

Inflammation is likely to represent a new target for both the treatment and prevention of acute myocardial infarction

0

5

10

15

20

Statin Therapy, Lipid Levels, CRP, and Statin Therapy, Lipid Levels, CRP, and Survival Among Patients with Severe Survival Among Patients with Severe Coronary Artery DiseaseCoronary Artery Disease

Horne BD et al. J Am Coll Cardiol 2000;36:1774-1780.2000 Reprinted with permission from the American College of Cardiology.

CRP Tertiles StatinsStatins

Low

Mort

alit

y (

%)

CRP Tertiles No StatinsNo Statins

Medium High Low Medium High

PP Trend = Trend = 0.940.94

PP Trend Trend <0.0001<0.0001

Short-Term Effects of Statins on Short-Term Effects of Statins on hs-CRP Levelshs-CRP Levels

Randomized, double-blind, crossover trial with 22 hyperlipidemic patients (LDL-C >130, TG 200-600 mg/dL)

6 weeks of therapy with either simvastatin 20 mg, atorvastatin 10 mg, or pravastatin 40 mg

3-week washout between drugs

Jialal I et al. Circulation 2001;103:1933-1935.

Effect of Statin Therapy on Lipid and Effect of Statin Therapy on Lipid and Lipoprotein Levels at 6 WeeksLipoprotein Levels at 6 Weeks

Jialal I et al. Circulation 2001;103:1933-1935.

Baseline Pravastatin Simvastatin Atorvastatin

TC 264.3+36.9 219.7+37.8* 201.0+35.1* 191.5+33.5*

LDL-C 169.7+37.1 132.8+35.4* 118.3+30.2* 113.8+28.4*

HDL-C 44.7+13.2 45.8+12.8 45.7+13.4 44.8+12.5

TG 230.3(144-588)

178.8(97-1352)

164.0(91-400)*

162.3(87-581)*

Mean +SD or median (range), mg/dL*P<0.001 vs. baseline

hs-

CR

P (

mg/L

)Effect of Statin Therapy on hs-CRP Levels Effect of Statin Therapy on hs-CRP Levels at 6 Weeksat 6 Weeks

Jialal I et al. Circulation 2001;103:1933-1935.2001 Lippincott Williams & Wilkins.

6

5

4

3

2

1

0 Baseline

* * *

Prava(40 mg/d)

Simva(20 mg/d)

Atorva(10 mg/d)

*p<0.025 vs. Baseline

Effect of Cerivastatin on CRP Levels in Effect of Cerivastatin on CRP Levels in Patients with HypercholesterolemiaPatients with Hypercholesterolemia


-13.3 -11.1 -13.3

-41.0-37.3

-42.2

7.8 6.7 8.0

-50.0

-40.0

-30.0

-20.0

-10.0

0.0

10.0

20.0

Chan

ge a

t 8 w

eeks

, %

n=785 n=623n=162

All patients 0.4 mg 0.8 mg

CRP LDL-C HDL-C

Effect of Pravastatin on CRP Levels in Effect of Pravastatin on CRP Levels in Primary and Secondary Prevention: Primary and Secondary Prevention: PRINCEPRINCE

-16.0-14.0-12.0-10.0-8.0-6.0-4.0-2.00.0

Primary Prevention

Chan

ge in

CR

P,

%

Secondary Prevention

* *

*

****

Albert MA et al. JAMA 2001;286:64-70.

12 weeksvs. baseline

24 weeksvs. baseline

24 weeks ITTvs. placebo

*p<.001vs.

baseline

**p<.005vs.

baseline

Effect of Bezafibrate with and without Fluvastatin Effect of Bezafibrate with and without Fluvastatin on Plasma Fibrinogen, PAI-1, and CRP in Patients on Plasma Fibrinogen, PAI-1, and CRP in Patients with CAD and Mixed Hyperlipidemiawith CAD and Mixed Hyperlipidemia

Beza 400 mg/d

Beza 400 mg/d+ fluva 20 mg/d

Beza 400 mg/d+ fluva 40 mg/d

Cortellaro M et al. Thromb Haemost 2000;83:549-553.

-20-15-10

-505

1015

Chan

ge a

t 24

weeks

, %

n: 81

Fibrinogen PAI-1 CRP

80 74

70 72 63 83 80 75

P<0.05 vs. baseline**

*

Effect of Gemfibrozil and Ciprofibrate on Plasma Effect of Gemfibrozil and Ciprofibrate on Plasma Fibrinogen and CRP Levels in Patients with Fibrinogen and CRP Levels in Patients with Primary HypercholesterolemiaPrimary Hypercholesterolemia

de Maat MPM et al. Thromb Haemost 1997;77:75-79.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40Pretreatment 12 Weeks

*

*

Fib

rin

og

en

, g

/L CR

P, m

g/L

Gemfibrozil600 mg bid

(n=51)

Ciprofibrate100 mg/d

(n=48)

Gemfibrozil600 mg bid

(n=51)

Ciprofibrate100 mg/d

(n=48)

*p<0.005 vs. pretreatment level

SummarySummary

Lifestyle modification and some pharmacotherapies (full-dose ASA, statins) lower hs-CRP

Lipid-modifying therapies with oral estrogens and fibrates are not associated with reduction in hs-CRP

Individuals with high levels of hs-CRP are at increased risk for CHD events and benefit from ASA and statins

Documents

Inflammatory Markers, Pharmacotherapy, and Clinical Trials Paul M. Ridker, M.D., M.P.H., and Christie M. Ballantyne, M.D