1. Pleiotropic Effects of Statins Rabih R. Azar, MD, MSc, FACC Division of Cardiology Hotel Dieu de France Hospital

2. Pleiotropic Effects of Statins Statins block the biosynthesis of cholesterol This mechanism explains theid main benefit However, they are also beneficial in patients with normal cholesterol In addition, a substantial quantity of data show that statins exert various effects on multiple targets and which are INDEPENDENT of their cholesterol lowering properties These are called the PLEOTROPIC EFFECTS of statins

3. Mechanisms of the Pleiotropic Effects of Statins Improved endothelial function Anti-thrombotic effect Reduced inflammation

4. Mechanisms of the Pleiotropic Effects of Statins Improved endothelial function Improved endothelial function Anti-thrombotic effect Reduced inflammation

5. Normal Endothelial Function

6. 60 pts with acute coronary syndromes and hypercholesterolemia randomized to placebo or pravastatin 40 mg/d for 6 weeks Flow-mediated dilatation measured by brachial artery ultrasound at baseline and 6 weeks Total C decreased by 14% and LDL-C by 26% in pravastatin group during treatment Cholesterol Reduction Improves Endothelial Function After ACS: The RECIFE Trial Dupuis et al. Circulation. 1999;99:3227-3233.

7. * Cholesterol Lowering Improves Flow-Mediated Dilatation After ACS: The RECIFE Trial % Placebo Pravastatin Time 06 Weeks 12 10 8 6 4 2 0 Time 06 Weeks 8 7 6 5 4 3 2 Flow-mediated DilatationNitroglycerin Dilatation *p<0.05

8. Effect of Cerivastatin on Endothelial Function 27 elderly diabetic patients With or without mild hypercholesterolemia 3 days treatment with low dose cerivastatin (0.15 mg/day) Levels of plasma lipids were not changed Tsunekawa, circulation 2001;104:376-379

9. Effects of Cerivastatin on Brachial Artery Flow P < 0.05 Endothelial dependent dilation NTG dependent dilation Controls Ceriva 3 days Ceriva 3 months Tsunekawa, circulation 2001;104:376-379 P = NS P = NS

10. Effects of Cerivastatin on Plasma cGMP Levels P < 0.05 P = NS Tsunekawa, circulation 2001;104:376-379

11. Activation of eNos by Statins NO Concentration (nM) 180 150 120 90 60 30 0 *+* + ACETYLCHOLINE * ++ * PRAVASTATIN * * SIMVASTATIN** Basal Release 0.1 µM Agent 1 µM Agent 10 µM Agent * Indicates difference form basal release (control); + indicates difference for response at 0.1 µmol/liter, p < 0.05. Kaesemeyer, et al JACC 1999;33:234-41.

12. Improved capacity for vasodilatation – improved regional blood flow and O 2 delivery An increase in NO decreases thrombogenicity – inhibits platelet adhesion and deposition – favorably affects the balance between PA and PAI NO inhibits inflammation within the vessel wall Potential Benefits of Improved Endothelial Function in Acute Coronary Syndromes

13. Mechanisms of the Pleiotropic Effects of Statins Improved endothelial function Anti-thrombotic effect Reduced inflammation

14. Pravastatin Reduces Markers of Thrombosis in Hypercholesterolemic Patients Hypercholesterolemic patients (mean cholesterol 258 mg/dL, mean LDL 170 mg/dL) Pravastatin 40mg/day vs. placebo for 8 weeks P < 0.02 F VIIa, mU/mL F1+2 nmol/L Cipollone et al. Circulation 2002;106:399-402

15. Effects of Pravastatin on Markers of Thrombosis in the RECIFE Trial MarkerEffect Thrombin anti-thrombinNo change PAI-1No change Von Willbrand factorNo change Tissue FactorNo change TFPINo change Total GP IIb/IIIaNo change Factor VIINo change Dupuis et al. Circulation. 1999;99:3227-3233.

16. Effects of Cerivastatin on von Willbrand Factor Tsunekawa, circulation 2001;104:376-379 P = NS

17. % Change in Fibrinogen from Baseline -20-10010203040 50 Pravastatin (n = 3510) Simvastatin (n = 364) Atorvastatin (n = 1083) 60 Lovastatin (n = 615) Variable Effects of Statins on Fibrinogen Atorvastatin: Marais AD 1997; Davidson M 1997; Wierzicki AS 1998; Nair 1998; Stein 1998; Lovastatin: Sinzinger H 1995; Koenig W 1992; Beigel Y 1991 (2); Koppensteiner R 1990; Illingworth DR 1992; Stein 1998; Simvastatin: McDowell IF 1991; Steinmetz A 1996; Kehely A 1995; Farnier M 1994; Illingworth DR 1992; Branchi 1993; Stein 1998; Pravastatin: Lowe G 1998 (personal communication); Salonen 1995; Fogari R 1997; Tsuda Y 1996; Avellone G 1994; Tsuda Y 1993; Branchi A 1993; Wada H 1992; Jay RH 1990; Stein 1998;

18. 16 hypercholesterolemic coronary pts and 16 coronary pts with normal cholesterol levels (<200 mg/dL) Thrombus formation assessed by exposing porcine aortic media (simulating plaque rupture) to the pt’s flowing venous blood x 3 mins at low and high shear rates, using an ex vivo superfusion chamber Tests repeated in hypercholesterolemic pts after 1 week and 2.4 months of pravastatin 40 mg/d Cholesterol Levels and Platelet Thrombus Deposition Lacoste L et al. Circulation. 1995;92:3172-3177.

19. Cholesterol Levels and Platelet Thrombus Deposition *p<0.05 normocholesterolemic vs hypercholesterolemic (basal) at both shear rates. † p<0.05 basal vs after pravastatin at both shear rates. Lacoste L et al. Circulation. 1995;92:3172-3177. Platelet deposition (µm 2 /mm) 6 5 4 3 2 1 0 NormocholBasalAfter prava Hypercholesterolemic 6 5 4 3 2 1 0 NormocholBasalAfter prava Hypercholesterolemic Shear Rate 754 S -1 Shear Rate 2346 S -1 * * † †

20. The shedding of sCD40L during platelets stimulation

21. Effects of sCD40L Initiation of the inflammatory response – Expression of ICAM, VICAM, E-selectin – Expression of chemokines (IL-6, IL-6, MCP-1) Prothrombotic effect – Expression of tissue factor – Interaction with the GP IIb/IIIa receptor Progression of atherosclerosis

22. Levels of sCD40L are increased in unstable angina suggesting that it may have a role in plaque destabilization (Circulation 1999;100:614-620) sCD40L levels in different clinical conditions

23. Cerivastatin and Pravastatin Reduce soluble CD40 ligand Levels in Hypercholesterolemic Patients P = NS P < 0.05 P = NS P < 0.02 sCD40l, ng/mL Cipollone et al. Circulation 2002;106:399-402

24. Mechanisms of the Pleiotropic Effects of Statins Improved endothelial function Anti-thrombotic effect Reduced inflammation Reduced inflammation

25. Unstable Plaques are Hot. CRP probably identifies vulnerable plaques Difference of temp from background temp Stefanadis. Circ 99;99:1965

26. Sources of Inflammatory Markers

27. Risk of MI According to CRP Levels

28. Atorvastatin Enhances the Decline in CRP in Patients with Acute Coronary Syndromes (MIRACL) P < 0.01 P = NS P < 0.001 Mean hs-CRP Values Mean Change in hs-CRP Mean hs-CRP Values Mean Change in hs-CRP Kinlay et al. Circulation 2003;108:1560-1566

29. Simvastatin lowers CRP within 14 days An effect independent of LDL cholesterol reduction day 0 day 0 day 14 day 14 Median CRP Plenge et al. Circ 2002;106:1447-52 P = NS P = 0.01

30. Coronary Angioplasty Induces a Systemic Inflammatory Response Mean CRP mg/L P < 0.001 P = NS Azar et al. Am J Cardiol 1997;80:1476-8

31. Effects of Statin Therapy on the Rise of Markers of Inflammation and on Platelets Activation Following Angioplasty P = 0.008 Azar et al. Submitted to circulation 2004

32. Statin therapy at the time of PCI confers an early and sustained survival benefit Chan et al. Circulation 2002;105:691-696

33. Mortality according to baseline CRP and statins use following PCI 1-year mortality (%) P = NS P < 0.009 Preprocedural CRP Chen et al. Circulation 2003;107:1750-1756

34. Statins suppress elevation of hs-CRP following angioplasty in patients with high levels of hs-CRP at baseline Azar et al. Submitted to circulation 2004

35. Pleiotropic Effects of Statins ARE THEY CLINICALLY RELEVANT?

36. 0 2 4 6 8 10 12 14 12345 WOSCOPS: Framingham Predicted vs Observed Event Rates: Placebo and Pravastatin Group 4.4 Year CHD Event Rate (%)* Quintiles of Risk * Predicted on the basis of on-treatment lipid levels PLACEBO PRAVASTATIN -- predicted 5.6%  observed 4.5% p = 0.026 -- predicted 7.4%  observed 7% p = 0.58

37. Withdrawal of statins increases event rates in patients with acute coronary syndromes Heeschen et al. Circulation 2002;105:1446-1452

38. Cholesterol lowering with atorvastatin 80 mg/d will reduce the incidence of ischemic events as compared to placebo in patients hospitalized with unstable angina or non-Q wave MI MIRACL Hypothesis

39. Double-blind, randomized, placebo-controlled trial in 3000 pts with unstable angina or non-Q MI Atorvastatin 80 mg/d or placebo begun 1-4 days after hospital admission and continued for 4 months Primary end point is a composite of death, nonfatal MI, resuscitated cardiac arrest, and recurrent, symptomatic myocardial ischemia with objective evidence requiring emergency hospitalization Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) Study Schwartz et al. Am J Cardiol. 1998;81:578.

40. MIRACL: Primary Efficacy Measure Relative risk = 0.84 P=0.048 95% CI 0.701-0.999 Atorvastatin Placebo 0 5 10 15 0481216 Time since randomization (weeks) Cumulative Incidence (%) Time to first occurrence of: Death (any cause) Non-fatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 17.4% 14.8%

41. MIRACL: Fatal or non-fatal stroke 0 0.5 1 1.5 2 0481216 Time since randomization (weeks) Cumulative Incidence (%) Relative risk = 0.50 P=0.045 95% CI 0.26-0.99 Atorvastatin Placebo 1.6% 0.8%

42. Pleiotropic Effects of Statins: Conclusions Yes, 2 of 3 are proved and may explain the benefits of statins beyond lipid lowering Yes, 2 of 3 are proved and may explain the benefits of statins beyond lipid lowering Improvement in endothelial function: PROVED Improvement in endothelial function: PROVED Anti-platelets and anti-thrombotic: ? Anti-platelets and anti-thrombotic: ? Anti-inflammatory: PROVED Anti-inflammatory: PROVED

43. Statin therapy reduced the number and volume of inflammatory lesions in multiple-sclerosis patients Vollmer et al. Lancet 2004;363:1607-08

44. Normal Endothelial Function

45. Effects of Cerivastatin on Plasma Nitrite/Nitrate (Nox) Concentration (μM) P < 0.05 Tsunekawa, circulation 2001;104:376-379 P = NS

46. CRP and Cholesterol in the Prediction of Cardiovascular Events

47. CRP Is a Risk Factor in Unstable Angina Liuzzo et al. N Engl J Med. 1994;331:417. CRP <0.3 mg/dL (n=11) CRP ≥0.3 mg/dL (n=20) p-value Ischemic episodes1.8±2.44.8±2.50.004 In-hospital events: Death02 MI05 Revascularization212 Total2 (18%)18 (90%)<0.001

48. Event Reduction in CARE According to Presence or Absence of Inflammatory Markers Ridker et al. Circulation. 1998;98:839. Relative risk 3 2 1 0 p trend = 0.005 Inflammation absent Pravastatin Inflammation absent Placebo Inflammation present Pravastatin Inflammation present Placebo Inflammation defined as CRP and SAA ≥90th percentile