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

2. Is there clinical evidence that inflammation can be modified by preventive therapies?

3. hs-CRP, Aspirin, and Risks of Future MI: Physicians' 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 1234 Aspirin Placebo Relative Risk of MI

4. Low-Dose Aspirin Reduces Thromboxane B 2 but not CRP Serum CRP (% of Baseline) 140 120 100 80 60 40 20 0 Placebo (n=11) Feldman M et al. J Am Coll Cardiol 2001;37:2036-2041. 140 120 100 80 60 40 20 0 Serum Thromboxane (% of Baseline) ASA 81 mg qd (n=13) Placebo (n=11) ASA 81 mg qd (n=13) 28 Days 31 Days * p<0.001 *

5. Reduction of Proinflammatory Cytokines and CRP with Higher-Dose Aspirin in Patients 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/mL1.4 (0.54-4.05) 1 (0.5-3.1) <0.05

6. Elevated CRP Levels in Obesity: NHANES 1988-1994 Visser M et al. JAMA 1999;282:2131-2135. Normal Percent with CRP 0.22 mg/dL OverweightObese

7. Effects of Weight Loss on CRP Concentrations in Obese Healthy Women 83 women (mean BMI 33.8, range 28.2-43.8 kg/m 2 ) 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.

8. Effects of Weight Loss in Obese Women on IL-6, TNF-, and CRP Bastard J-P et al. J Clin Endocrinol Metab 2000;85:3338-3342. pg/mL mg/L IL-6 TNF- CRP Before diet After very low calorie diet (mean BMI reduction 2.1 kg/m 2 ; mean reduction in body fat mass 4 kg) p=0.05 p=0.6 p=0.14

9. Effects of n-3 Fatty Acid Therapy on Lipids and sCAMs Percent Change Abe Y et al. Arterioscler Thromb Vasc Biol 1998;18:723-731. TGTCsICAM-1sE-selectin All Patients DM Patients * * * * * p<0.05

10. Effect of ACE Inhibition vs. Angiotensin II Receptor Blockade on sCAMs and CRP in Type 1 Diabetics with Diabetic Nephropathy Andersen S et al. Diabetes Care 2000;23:1031-1032. Placebo Losartan 50 mg Losartan 100 mg Enalapril 10 mg Enalapril 20 mg *p<0.05 vs. placebo * * * sVCAM-1, ng/ml sICAM-1, ng/ml

11. Effect of ACE Inhibition vs. Angiotensin II Receptor Blockade on sCAMs and CRP in Type 1 Diabetics with Diabetic Nephropathy Placebo Losartan 50 mg Losartan 100 mg Enalapril 10 mg Enalapril 20 mg *p<0.05 vs. placebo * * sE-selectin, ng/ml CRP, ng/ml Andersen S et al. Diabetes Care 2000;23:1031-1032.

12. Effect of HRT on hs-CRP: the PEPI Study 3.0 2.0 1.0 hs-CRP (mg/dL) Months 01236 Cushman M et al. Circulation 1999;100:717-722. 1999 Lippincott Williams & Wilkins. CEE + MPA cyclic CEE + MPA continuous CEE + MP CEE Placebo

13. hs-CRP and Relative Risk of Recurrent Coronary Events: CARE Ridker PM et al. Circulation 1998;98:839-844. 1998 Lippincott Williams & Wilkins. 1 <0.12 Relative Risk Quintile of hs-CRP (range, mg/dL) P=0.02 2 0.12-0.20 3 0.21-0.37 4 0.38-0.66 5 >0.66 P Trend = 0.044

14. Inflammation, Pravastatin, and Relative Risk of Recurrent Coronary Events: CARE Ridker PM et al. Circulation 1998;98:839-844. 1998 Lippincott Williams & Wilkins. Pravastatin Relative Risk Inflammation Absent P Trend = 0.005 PlaceboPravastatinPlacebo Inflammation Present

15. Mean Baseline (mg/dL) Inflammation absent Inflammation present 250 200 150 100 50 0 TCLDL-CHDL-CTG Baseline Lipid Levels in Patients with and without Inflammation: CARE Ridker PM et al. Circulation 1998;98:839-844.

16. Long-Term Effect of Pravastatin on hs-CRP: CARE Placebo and Pravastatin Groups Adapted from Ridker PM et al. Circulation 1999;100:230-235. 1999 Lippincott Williams & Wilkins. Pravastatin Placebo Median hs-CRP Concentration (mg/dL) –21.6% (P=0.007) 0.25 0.24 0.23 0.22 0.21 0.20 0.19 0.18 Baseline5 Years

17. Change in hs-CRP Concentration Over 5 Years: CARE Subgroup Analyses Change in hs-CRP over 5 Years (mg/dL) HDL-C <35 mg/dL All Subjects Pravastatin Age >60 years Age <60 years BMI >27 kg/m 2 BMI <27 kg/m 2 Placebo Smokers Nonsmokers SBP >128 mm Hg SBP <128 mm Hg DBP >78 mm Hg DBP <78 mm Hg LDL-C >138 mg/dL LDL-C <138 mg/dL HDL-C >35 mg/dL Triglycerides >160 mg/dL Triglycerides <160 mg/dL -0.2-0.100.10.20.3 Ridker PM et al. Circulation 1999;100:230-235.

18. Change in hs-CRP according to Observed Changes in LDL-C: CARE Placebo and Pravastatin Groups Change in LDL-C (mg/dL) Increase 0–25 Decrease 0–25 Decrease 25–50 Decrease 50–75 Decrease >75 Change in hs-CRP (mg/dL) Placebo Pravastatin -0.15 -0.10 -0.05 0 0.05 0.10 0.15 Ridker PM et al. Circulation 1999;100:230-235. 1999 Lippincott Williams & Wilkins.

19. Relative Risks of Future MI among Apparently Healthy Middle-Aged Men: Physician’s Health Study Relative Risk for Future MI 0 1.02.04.06.0 Lipoprotein(a) Homocysteine Fibrinogen tPA Antigen hs-CRP hs-CRP + TC/HDL-C Total Cholesterol TC:HDL-C Ridker PM. Ann Intern Med 1999;130:933-937. 1999 ACP-ASIM.

20. CRP in Combination with LDL-C as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Ridker PM et al. N Engl J Med 2001;344:1959-1965. Study GroupLovastatinPlaceboNNT Low LDL-C/low CRP0.0250.022_ Low LDL-C/high CRP0.0290.05148 High LDL-C/low CRP0.0200.05033 High LDL-C/high CRP0.0380.05558 Median LDL-C = 149.1 mg/dL Median CRP = 0.16 mg/dL Event Rate

21. CRP in Combination with TC:HDL-C Ratio as a Method to Target Statin Therapy in Primary Prevention: AFCAPS/TexCAPS Ridker PM et al. N Engl J Med 2001;344:1959-1965. Study GroupLovastatinPlaceboNNT Low TC:HDL-C/low CRP0.0240.025983 Low TC:HDL-C/high CRP0.0250.05043 High TC:HDL-C/low CRP0.0210.05035 High TC:HDL-C/high CRP0.0410.05762 Median TC:HDL-C = 5.96 Median CRP = 0.16 mg/dL Event Rate

22. hs-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

23. Statin Therapy, Lipid Levels, CRP, and Survival Among Patients with Severe Coronary Artery Disease Horne BD et al. J Am Coll Cardiol 2000;36:1774-1780. 2000 Reprinted with permission from the American College of Cardiology. Statins CRP Tertiles Statins Low Mortality (%) No Statins CRP Tertiles No Statins MediumHighLowMediumHigh P Trend = 0.94 P Trend <0.0001

24. Short-Term Effects of Statins on hs-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.

25. Effect of Statin Therapy on Lipid and Lipoprotein Levels at 6 Weeks Jialal I et al. Circulation 2001;103:1933-1935. BaselinePravastatinSimvastatinAtorvastatin TC264.3+36.9219.7+37.8*201.0+35.1*191.5+33.5* LDL-C169.7+37.1132.8+35.4*118.3+30.2*113.8+28.4* HDL-C44.7+13.245.8+12.845.7+13.444.8+12.5 TG230.3 (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

26. hs-CRP (mg/L) Effect of Statin Therapy on hs-CRP Levels at 6 Weeks Jialal I et al. Circulation 2001;103:1933-1935. 2001 Lippincott Williams & Wilkins. 65432106543210 Baseline * ** Prava (40 mg/d) Simva (20 mg/d) Atorva (10 mg/d) *p<0.025 vs. Baseline

27. Effect of Cerivastatin on CRP Levels in Patients with Hypercholesterolemia Ridker PM et al. Circulation 2001;103:1191-1193. 2001 Lippincott Williams & Wilkins. Change at 8 weeks, % n=785 n=623 n=162 All patients0.4 mg0.8 mg CRPLDL-CHDL-C

28. Effect of Pravastatin on CRP Levels in Primary and Secondary Prevention: PRINCE Primary Prevention Change in CRP, % Secondary Prevention * * * ** Albert MA et al. JAMA 2001;286:64-70. 12 weeks vs. baseline 24 weeks vs. baseline 24 weeks ITT vs. placebo *p<.001 vs. baseline **p<.005 vs. baseline

29. Effect of Bezafibrate with and without Fluvastatin on Plasma Fibrinogen, PAI-1, and CRP in Patients with 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. Change at 24 weeks, % n: 81 FibrinogenPAI-1CRP 8074 707263838075 P<0.05 vs. baseline * * *

30. Effect of Gemfibrozil and Ciprofibrate on Plasma Fibrinogen and CRP Levels in Patients with Primary Hypercholesterolemia de Maat MPM et al. Thromb Haemost 1997;77:75-79. Pretreatment12 Weeks * * Fibrinogen, g/L CRP, mg/L Gemfibrozil 600 mg bid (n=51) Ciprofibrate 100 mg/d (n=48) Gemfibrozil 600 mg bid (n=51) Ciprofibrate 100 mg/d (n=48) *p<0.005 vs. pretreatment level

31. Summary 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