1. Lipid Management in Stroke : Statin and Other Lipid Modifying Agents Professor Pierre Amarenco INSERM U-698 and Paris-Diderot University Department of Neurology and Stroke Centre Bichat-Claude Bernard Hospital, Paris, France

2. *For the protective factor of physical activity, the population-attributable risks are provided for individuals who do not participate in regular physical activity. Risk factorPopulation-attributable risk, % (99% CI) Hypertension34.6 (30.4–39.1) Smoking18.9 (15.3–23.1) Waist-to-hip ratio (tertile 2 vs tertile 1)26.5 (18.8–36.0) Dietary risk score (tertile 2 vs tertile 1)18.8 (11.2–29.7) Regular physical activity28.5 (14.5–48.5) Diabetes5.0 (2.6–9.5) Alcohol intake3.8 (0.9–14.4) Cardiac causes6.7 (4.8–9.1) Ratio of apolipoprotein B to A1 (tertile 2 vs tertile 1) 24.9 (15.7–37.1) Psychological factors Stress 4.6 (2.1–9.6) Depression 5.2 (2.7–9.8) INTERSTROKE: Population-attributable risk for common risk factors O'Donnell MJ et al. Lancet 2010; available at: http://www.thelancet.com.

3. Meta-analysis : Statin and Stroke N total=165 732 Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

4. Meta-Analysis Stroke Death Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

5. Meta-analysis Hemorrhagic stroke Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

6. Stroke Risk and LDL Lowering Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI 6.3 to 33.5%, p<0.001) Total n=165,732 Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

7. JUPITER 64 (0.72%) 143 (1.6%) 251 (2.8%) Placebo * 48% (21-66) p=0.002 33 (0.37%)Stroke 47% (30-60)76 (0.85%) Revascularisation or Unstable angina 44% (31-54) p=0.000001 142 (1.6%)Primary endpoint Hazard Ratio Risk Reduction (CI)Rosuva *Event * N (% randomised).2.4.6.811.2 Favours Rosuvastatin Favours Placebo 68 (0.76%)54% (30-70)31 (0.35%)Any MI 157 (1.8%)47% (30-61)83 (0.93%)MI, Stroke, CVdeath N=17,802 LDL-c<130 mg/dL hsCRP >2 mg/dL F/U 1.9 yrs Men >50 yrs Women >60 yrs

8. Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mgNumber of events 89 (1.7%) PlaceboNumber of events121 (2.4%) 27% reduction HR = 0.73 (0.56-0.96)p=0.0236 0 1 2 3 0,00,51,01,52,02,53,03,5 Years Cumulative Incidence (%) Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

9. Placebo n=39 [31% of all first CVD events] Atorvastatin n=21 [25% of all first CVD events] (P=0.016) CARDS: Cumulative Hazard for Stroke 0 0 Years from Randomization Cumulative Hazard (%) 12344.75 1 2 3 4 48% Risk Reduction In Stroke Placebo Atorvastatin10 mg Hitman GA, et al. EASD Diabetologia. 2005; Abstract 120 Data on file, Pfizer Inc.

10. Pleiotropic Effects Studied Parameter Within the Plaque Lipid contain (Oil Red O) Ox-LDL (NA59) Macrophage contain T-Cell count SMC Apoptotic Cells (TUNEL) Control Group n=13 23.9% 22% 25.3% 23.4% 16.9% 32% Pravastatin Group n=11 8.2% 13.3% 15.3% 11.2% 24.3% 17.7% P Value <0.001 <0.05 Crisby et al. Circulation 2001

11. Between-Group LDL Reduction and Carotid- IMT Reduction Per Year For Each 10% LDL-cholesterol IMT reduction per year = 0.76% (95%CI, 0.34-1.18) r=0.70, p=0.0013 Amarenco et al. Stroke 2004;35:2902-9

12. Patient population Lacunar stroke 3 months prior rando Lacunar stroke 3 months prior rando 2-month Run-in period prior rando: 2-month Run-in period prior rando: BP treatment to target guidelines Blood glucose control if diabetic Double-blind placebo 94 patients Atorvastatin 80 mg Primary end point: Cerebral vasoreactivity Cerebral vasoreactivity 3 months Secondary end point: Brachial artery vasoreactivity Brachial artery vasoreactivity Randomization with stratification on hypertensive and diabetic status CVMR Lacunar B.I.C.H.A.T. Study Design L acunar B rain I nfarction, C erebral H yperreactivity, and A torvastatin T rial Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009

13. Primary and Secondary Endpoints TREATMENT BETTERTREATMENT WORSE PRIMARY ENDPOINT SECONDARY ENDPOINT Lavallée PC, Amarenco P for the Lacunar-B.I.C.H.A.T. investigators. Stroke. 2009

14. Stroke: Potential Mechanisms of Benefit LDL Reduction Plaque stabilization: macrophages smooth muscle cells immunologic response lipid core oxidized LDL Improved endothelial function Reduced hemorheologic stress Reduced platelet aggregation Reduced thrombotic and Enhanced fibrinolytic state Statin Blood pressure reduction Decrease incidence of MI and of left ventricular mural thrombus 35 to 80% of the benefit Neuroprotection. Up-regulation NO. Improves CBF. Reduces infarct size

15. HPS: No Reduction in Risk of Recurrent Stroke in Patients With Prior Cerebrovascular Disease *29% RR, P=.001 Heart Protection Study Collaborative Group. Lancet. 2004;363:757–767. Patient with Event (5) n=169n=170n=406n=488 Major Vascular EventsStroke

16. 4,731 Patients SPARCL: Study Design Placebo 540 Primary Endpoints Atorvastatin 80 mg/day Double-Blind Period Source: The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389–395 Primary End Point Time to the First Occurrence of a Fatal or Nonfatal Stroke Patient Population  205 sites worldwide  Previously documented stroke or TIA within 6 months  No history of CHD  LDL-C levels ≥100 mg/dL and ≤190 mg/dL

17. LCL-C During Follow-up Mean on-treatment LDL-C: Placebo = 129 mg/dL Atorvastatin = 73 mg/dL -53% +1% -7% -38% Baseline LDL-C: 133 mg/dL Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

18. Primary Endpoint: Time to Fatal or Non-Fatal Stroke Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03 16% RR Years Since Randomization Fatal or Non-Fatal Stroke (%) 0123456 0% 4% 8% 12% 16% Placebo Atorvastatin *Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

19. Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003 Secondary Endpoint: Time to Major Coronary Event 35% RR Years Since Randomization Major Coronary Event (%) 0123456 0% 2% 4% 6% 8% Placebo Atorvastatin *Treatment effect from Cox proportional hazards models with pre-specified adjustment for geographical region, entry event, time since entry event, gender, and baseline age. Amarenco P, Bogousslavsky J, Callahan A III, et al. N Engl J Med. 2006;355:549-59

20. Gender: Stroke Outcomes Pre-specified adjustment for region, entry event, time since entry event and age Goldstein LB, Amarenco P, Callahan A III, al.. Stroke. 2008;39:2444-48

21. SPARCL Elderly vs Young Chaturvedi S et al. Neurology. 2008 ;E-pub YOUNG ELDERLY STROKE CV events

22. SPARCL Elderly vs Young Chaturvedi S et al. Neurology. 2008 ;E-pub

23. Ischemic and Hemorrhagic Stroke Post hoc analysis Unadjusted HR Fatal and Non-fatal Stroke Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70

24. Multivariable Cox Regression Model Baseline Characteristics & Time Varying Blood Pressure Risk of hemorrhageOR (95% CI)p Atorvastatin treatment 1.69 (1.10, 2.60)0.02 Hemorrhage as entry event 5.81 (2.91, 11.60)<0.001 Male sex 1.77 (1.11, 2.81)0.02 Age (10 yr increments) 1.37 (1.12, 1.69)0.003 Blood Pressure Pre-hypertension Stage 1 hypertension Stage 2 hypertension 3.18 (0.76, 13.34) 3.49 (0.83, 14.61) 6.19 (1.47, 26.11) 0.01 0.11 0.09 0.01 Pre-HTN: SBP 120-139 or DBP 80-89 Stage 1: SBP 140-159 or DBP 90-99 Stage 2: SBP>160 or DBP>100 Treatment X entry event interaction, p=0.20 Treatment X hypertension interaction, p=0.25 Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70

25. Hazard ratio* *Adjusted for time since entry event, gender, and age -202468 HR (95% CI) P-value Large Vessel TIA Hemorrhagic 0.0556 Small Vessel Unknown 1.23 (0.44, 3.39) 0.97 (0.44, 2.17) 4.67 (0.96, 22.6) 5.07 (1.73, 14.9) 0.80 (0.30, 2.13) 0.6494 0.0031 0.6934 0.9473 Entry Event Atorvastatin better Placebo better Impact of Atorvastatin on Hemorrhagic stroke by Entry Event Goldstein LB, Amarenco P et al. Neurology. 2008;70:2864-70

26. Impact of Atorvastatin on Stroke Risk Stroke Large Vessel TIA Hemorrhagic Small Vessel Unknown 0.70 (0.49, 1.02) 0.81 (0.57, 1.17) 3.24 (1.01, 10.4) 0.85 (0.64, 1.12) 0.87 (0.61, 1.24) 0.0604 0.2639 0.0482 0.2491 0.4422 01234 Hazard Ratio HR (95% CI)p-value Amarenco et al. Stroke. 2009 P for heterogeneity = 0.421

27. Impact of Atorvastatin on Coronary Risk and Death Major Coronary Event Death Large Vessel TIA Hemorrhagic Small Vessel Unknown Large Vessel TIA Hemorrhagic Small Vessel Unknown 0.60 (0.29, 1.25) 0.70 (0.40, 1.25) 1.09 (0.15, 7.93) 0.80 (0.50, 1.27) 0.43 (0.24, 0.80) 0.77 (0.48, 1.22) 0.99 (0.68, 1.45) 2.24 (0.67, 7.55) 1.20 (0.86, 1.68) 0.84 (0.56, 1.27) 0.1690 0.2317 0.9324 0.3407 0.0071 0.2657 0.9615 0.1918 0.2799 0.4035 01234 Hazard Ratio HR (95% CI)p-value Amarenco et al. Stroke. 2009 P for heterogeneity = 0.360

28. Benefit/Risk Atorvastatin n = 2365 Placebo n = 2366 Atorvastatin n = 2365 Placebo n = 2366 Incidence (%) Stroke and Major Coronary Events Major Coronary Event Ischemic Stroke Hemorrhagic Stroke Unclassified Stroke Stroke P=0.03 11.2% 13.1% 14.1% 17.2% P=0.002 Amarenco P, et al. Exp Op Pharmacotherapy. 2007

29. 8.1 Ischemic Stroke Severity: Last Dose  1 Month Before Stroke Placebo (n=222) 42.8 32.4 11.3 13.5 MildFatalSevereModerate Improvement in atorvastatin group (%) 11.77.3 Atorvastatin (n=175) 50.9 36.06.96.3 Proportion of patients (%) 50.9 42.8 Results were similar after adjusting for age, gender, and severity of baseline event (P=0.044) P = 0.007 *Percent of patients with no recurrent event is not shown to scale. Subjects with missing severity for first event are excluded. Stroke severity determined by Rankin Scale: 0/1=mild, 2/3=moderate, 4/5=severe. Goldstein LG, Amarenco P et al. Stroke. 2009

30. Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes 70 100 90 80 Percentage of Patients Free of End Points Placebo Atorvastatin 80 mg 012345 Years since randomization 6 *Adjusted for entry event, time since entry event, gender, age, and geographic region HR=0.70 (95% CI 0.50, 0.98), P=0.0387* Log-rank P=0.0377 RR: 30% Callahan A, Welch KMA, Amarenco P, et al.

31. Effect of Atorvastatin on CV Events In SPARCL Patients with Diabetes Any CHD Event Any Revascularization Placebo Atorvastatin 80 mg Years since randomization Percentage of Patients Free of End Points 012345 6 82 100 84 86 88 90 92 94 96 98 Percentage of Patients Free of End Points 012345 6 82 100 84 86 88 90 92 94 96 98 Placebo Atorvastatin 80 mg Years since randomization *Adjusted for entry event, time since entry event, gender, age, and geographic region HR=0.49 (95% CI 0.31, 0.79), P=0.0033* Log-rank P=0.0027 RR: 51% HR=0.36 (95% CI 0.21, 0.61), P=0.0001* Log-rank P=0.0001 RR: 64% Callahan A, Welch KMA, Amarenco P, et al.

32. Effect of Atorvastatin on Renal Function by Glycemic Status * Treatment difference † Difference from baseline No Diabetes, No MetS Atorvastatin Placebo MetSDiabetes n=1459n=1476n=366n=359n=360n=370 p < 0.001* p = 0.012* Mean Change in eGFR from Baseline (mL/min/1.73 m 2 ) p = 0.001* -4.5 -4.0 -3.5 -3.0 -2.5 -2.0 -1.5 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 p = 0.258 † p < 0.0001 †

33. Stroke in Patients With Carotid Stenosis HR=0.67 (95% CI 0.47, 0.94), P=.02* 012345 70 100 90 80 Patients free of fatal or non-fatal stroke (%) Years since randomization Placebo Atorvastatin *: adjusted for entry event, time since entry event, gender, age, and geographical region RR: 33% Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

34. 012345 50 80 90 100 60 70 Any Cardiovascular Event in patients With Carotid Stenosis HR=0.58 (95% CI 0.46, 0.73), P<.0001 Patients free of any cardiovascular event (%) Years since randomization Placebo Atorvastatin *: adjusted for entry event, time since entry event, gender, age, and geographical region RR: 42% Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

35. 012345 98 100 92 94 96 Carotid Endarterectomy in Patients With Carotid Stenosis HR=0.44 (95% CI 0.24, 0.79), P=.006 Patients free of carotid endarterectomy (%) Placebo (n=37/514) Atorvastatin (n=16/493) Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region RR: 56% Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

36. Stroke Risk and LDL Lowering Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI 6.3 to 33.5%, p<0.001) N total=165 732 Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

37. Stroke Risk and LDL Lowering Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI 6.3 to 33.5%, p<0.001) N total=165 732 Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

38. Time Varying LDL-C and Stroke Risk Note: Percent change effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase 0.40.71.01.31.61.92.2 <50% Decrease ≥50% Decrease <50% Decrease ≥50% Decrease <50% Decrease ≥50% Decrease HR (95% CI) 0.89 (0.73, 1.08) 0.69 (0.55, 0.87) 0.90 (0.73, 1.12) 0.67 (0.52, 0.86) 0.84 (0.50, 1.40) 1.04 (0.61, 1.78) p-value 0.2253 0.0016 0.3394 0.0018 0.4716 0.8864 All Stroke Ischemic Stroke Hemorrhagic Stroke Hazard Ratio (95% CI) ≥0% Increase1.00 ≥0% Increase1.00 ≥0% Increase1.00 Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204

39. Time Varying LDL-C and Stroke Risk Note: Nominal value effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase 0.40.71.01.31.61.92.2 70 to < 100 mg/dL < 70 mg/dL HR (95% CI) 1.01 (0.81, 1.27) 0.72 (0.59, 0.89) p-value 0.9076 0.0016 All Stroke Hazard Ratio (95% CI) ≥ 100 mg/dL1.00 Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204

40. Meta-analysis: Intensive LDL-C Lowering vs. Standard Statin Therapy Fatal and Nonfatal STROKE Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

41. Meta-analysis: Intensive Lipid-Lowering vs. Standard Statin Therapy MAJOR CARDIOVASCULAR EVENTS Amarenco P, Labreuche J. Lancet Neurol. 2009; 8:453-63

42. SBP DBP 140.0 139.5 139.0 138.5 137.5 81.5 138.0 137.0 82.0 81.0 80.5 80.0 1.0 0.0 LO7266605448423630241812630 Blood Pressure (mm Hg) Time (months) LDL HDL TG 150 125 100 75 50 25 0 LO7266605448423630241812630 Time (months) Lipids (mg/dl) LO = last observation Mean Lipids and BP During Follow-up in Atorvastatin and Placebo Groups Solid lines = atorvastatin 80 mg group; dashed lines = placebo group Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009

43. Optimal Multi-Targets  LDL-C <70 mg/dL (NCEP-III, high risk)  TG <150 mg/dL (normal ATP-III level)  HDL-C >50 mg/dL (NCEP-III)  BP <120/80 mm Hg (JNC-7) Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009

44. Combined Effect of Optimal Lipid & BP Control on Risk of Stroke and MCVE Stroke 0 parameters 1 parameter 2 parameters 3 parameters 4 parameters Major cardiovascular events (MCVE) 0 parameter 1 parameters 2 parameters 3 parameters 4 parameters No. subjects 662 1156 1926 906 80 662 1156 1926 906 80 No (%) events 93 (14.0) 167 (14.4) 228 (11.8) 84 (9.3) 4 (5.0) 126 (19.0) 207 (17.9) 290 (15.1) 114 (12.6) 4 (5.0) HR 1.00 0.982 0.782 0.620 0.354 1.000 0.903 0.725 0.603 0.247 95% CI (0.761, 1.266) (0.612, 0.998) (0.459, 0.837) (0.130, 0.963) (0.723, 1.128) (0.587, 0.896) (0.466, 0.781) (0.091, 0.669) P -value 0.8859 0.0478 0.0018 0.0420 0.3704 0.0029 0.0001 0.0059 Overall P -value* 0.0012 <0.0001 0.0 0.5 1.0 1.5 *P value for differences between number of parameters achieved Amarenco P, et al. Stroke. 2009