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L ipid M anagement i n S troke : S tatin a nd O ther L ipid M odifying A gents

L ipid M anagement i n S troke : S tatin a nd O ther L ipid M odifying A gents. Professor Pierre Amarenco INSERM U-698 and Paris-Diderot University Department of Neurology and Stroke Centre Bichat-Claude Bernard Hospital, Paris, France.

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L ipid M anagement i n S troke : S tatin a nd O ther L ipid M odifying A gents

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  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. INTERSTROKE: Population-attributable risk forcommon risk factors *For the protective factor of physical activity, the population-attributable risks are provided for individuals who do not participate in regular physical activity. 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. N=17,802 LDL-c<130 mg/dL hsCRP >2 mg/dL F/U 1.9 yrs JUPITER Men >50 yrs Women >60 yrs Event Rosuva * Placebo * Hazard Ratio Risk Reduction (CI) Primary endpoint 142 (1.6%) 251 (2.8%) 44% (31-54) p=0.000001 Any MI 31 (0.35%) 68 (0.76%) 54% (30-70) Stroke 33 (0.37%) 64 (0.72%) 48% (21-66) p=0.002 Revascularisation or Unstable angina 76 (0.85%) 143 (1.6%) 47% (30-60) MI, Stroke, CVdeath 83 (0.93%) 157 (1.8%) 47% (30-61) .2 .4 .6 .8 1 1.2 Favours Rosuvastatin Favours Placebo * N (% randomised)

  8. Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 (1.7%) Placebo Number of events 121 (2.4%) 3 27% reduction 2 Cumulative Incidence (%) 1 HR = 0.73 (0.56-0.96) p=0.0236 0 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Years Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58

  9. CARDS:Cumulative Hazard for Stroke 4 Atorvastatin10 mg 48% RiskReduction In Stroke Placebo Placebo n=39 [31% of all first CVD events] 3 (P=0.016) Cumulative Hazard (%) 2 1 Atorvastatin n=21 [25% of all first CVD events] 0 0 1 2 3 4 4.75 Years from Randomization 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 <0.001 <0.05 <0.05 <0.05 <0.05 Crisby et al. Circulation 2001

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

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

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

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

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

  16. SPARCL: Study Design Patient Population Double-Blind Period Atorvastatin 80 mg/day • 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 4,731Patients Placebo 540 Primary Endpoints Primary End PointTime to the First Occurrence of a Fatal or Nonfatal Stroke Source: The SPARCL Investigators. Cerebrovasc Dis. 2003;16:389–395

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

  18. 16% 16%RR Placebo Atorvastatin 12% Fatal or Non-Fatal Stroke (%) 8% 4% Adjusted HR (95% CI)* = 0.84 (0.71, 0.99), p = 0.03 0% 0 1 2 3 4 5 6 Years Since Randomization Primary Endpoint:Time to Fatal or Non-Fatal Stroke * 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. Secondary Endpoint:Time to Major Coronary Event 8% 6% 35%RR Major Coronary Event (%) 4% Placebo Atorvastatin 2% Adjusted HR (95% CI)* = 0.65 (0.49, 0.87), p = 0.003 0% 0 1 2 3 4 5 6 Years Since Randomization * 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 ELDERLY YOUNG STROKE CV events Chaturvedi S et al. Neurology. 2008 ;E-pub

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

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

  24. Multivariable Cox Regression ModelBaseline Characteristics & Time Varying Blood Pressure Treatment X entry event interaction, p=0.20 Treatment X hypertension interaction, p=0.25 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 Goldstein LB, Amarenco P, Szarek M, al. Neurology. 2008 ;70:2364-70

  25. Entry Event P-value HR (95% CI) Large Vessel 1.23 (0.44, 3.39) 0.6934 0.97 (0.44, 2.17) 0.9473 TIA 4.67 (0.96, 22.6) Hemorrhagic 0.0556 Small Vessel 5.07 (1.73, 14.9) 0.0031 0.80 (0.30, 2.13) Unknown 0.6494 - 2 0 2 4 6 8 Impact of Atorvastatin onHemorrhagic stroke by Entry Event Goldstein LB, Amarenco P et al. Neurology. 2008;70:2864-70 Hazard ratio* *Adjusted for time since entry event, gender, and age Placebo better Atorvastatin better

  26. Impact of Atorvastatin on Stroke Risk HR (95% CI) p-value Large Vessel 0.70 (0.49, 1.02) 0.0604 TIA 0.81 (0.57, 1.17) 0.2639 Hemorrhagic 3.24 (1.01, 10.4) 0.0482 Stroke Small Vessel 0.85 (0.64, 1.12) 0.2491 Unknown 0.87 (0.61, 1.24) 0.4422 P for heterogeneity = 0.421 0 1 2 3 4 Hazard Ratio Amarenco et al. Stroke. 2009

  27. Impact of Atorvastatinon Coronary Risk and Death HR (95% CI) p-value Large Vessel 0.60 (0.29, 1.25) 0.1690 Major Coronary Event TIA 0.70 (0.40, 1.25) 0.2317 Hemorrhagic 1.09 (0.15, 7.93) 0.9324 Small Vessel 0.80 (0.50, 1.27) 0.3407 Unknown 0.43 (0.24, 0.80) 0.0071 P for heterogeneity = 0.360 Large Vessel 0.77 (0.48, 1.22) 0.2657 TIA 0.99 (0.68, 1.45) 0.9615 Death Hemorrhagic 2.24 (0.67, 7.55) 0.1918 Small Vessel 1.20 (0.86, 1.68) 0.2799 Unknown 0.84 (0.56, 1.27) 0.4035 0 1 2 3 4 Hazard Ratio Amarenco et al. Stroke. 2009

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

  29. Ischemic Stroke Severity: Last Dose 1 Month Before Stroke Goldstein LG, Amarenco P et al. Stroke. 2009 Mild Moderate Severe Fatal Placebo (n=222) 32.4 13.5 11.3 42.8 42.8 Atorvastatin(n=175) 36.0 6.9 6.3 50.9 50.9 P = 0.007 Proportion of patients (%) Improvement in atorvastatin group (%) 8.1 11.7 7.3 Results were similar after adjusting for age, gender, and severity of baseline event (P=0.044) *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.

  30. Placebo Atorvastatin 80 mg Effect of Atorvastatin on Stroke In SPARCL Patients with Diabetes 100 90 Percentage of Patients Free of End Points RR: 30% 80 HR=0.70 (95% CI 0.50, 0.98), P=0.0387* Log-rank P=0.0377 70 0 1 2 3 4 5 6 Years since randomization *Adjusted for entry event, time since entry event, gender, age, and geographic region Callahan A, Welch KMA, Amarenco P, et al.

  31. 100 100 Placebo Placebo Atorvastatin 80 mg Atorvastatin 80 mg 98 98 96 96 94 94 92 92 90 90 88 88 86 86 84 84 82 82 Effect of Atorvastatin on CV EventsIn SPARCL Patients with Diabetes Any Revascularization Any CHD Event Percentage of Patients Free of End Points Percentage of Patients Free of End Points RR: 64% RR: 51% HR=0.49 (95% CI 0.31, 0.79), P=0.0033* Log-rank P=0.0027 HR=0.36 (95% CI 0.21, 0.61), P=0.0001* Log-rank P=0.0001 0 1 2 3 4 5 0 1 2 3 4 5 6 6 Years since randomization Years since randomization *Adjusted for entry event, time since entry event, gender, age, and geographic region Callahan A, Welch KMA, Amarenco P, et al.

  32. Effect of Atorvastatin on Renal Function by Glycemic Status p = 0.012* Atorvastatin 2.5 Placebo 2.0 p = 0.001* 1.5 1.0 0.5 p = 0.258† p < 0.0001† 0.0 Mean Change in eGFR from Baseline (mL/min/1.73 m2) -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0 -4.5 p < 0.001* n=1459 n=1476 n=366 n=359 n=360 n=370 No Diabetes, No MetS MetS Diabetes * Treatment difference † Difference from baseline

  33. Placebo Atorvastatin Stroke in Patients With Carotid Stenosis 100 90 Patients free of fatal or non-fatal stroke (%) RR: 33% 80 HR=0.67 (95% CI 0.47, 0.94), P=.02* 70 0 1 2 3 4 5 Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

  34. 100 Placebo Atorvastatin 90 80 70 60 50 0 1 2 3 4 5 Any Cardiovascular Event inpatients With Carotid Stenosis Patients free of any cardiovascular event (%) RR: 42% HR=0.58 (95% CI 0.46, 0.73), P<.0001 Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region Sillesen H, Amarenco P, Hennerici MG, et al. Stroke. 2009;40:E-pub

  35. 100 Placebo (n=37/514) Atorvastatin (n=16/493) 98 96 94 92 0 1 2 3 4 5 Carotid Endarterectomy inPatients With Carotid Stenosis Patients free of carotid endarterectomy (%) RR: 56% HR=0.44 (95% CI 0.24, 0.79), P=.006 Years since randomization *: adjusted for entry event, time since entry event, gender, age, and geographical region 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 HR (95% CI) p-value All Stroke ≥0% Increase 1.00 <50% Decrease 0.89 (0.73, 1.08) 0.2253 ≥50% Decrease 0.69 (0.55, 0.87) 0.0016 Ischemic Stroke ≥0% Increase 1.00 <50% Decrease 0.90 (0.73, 1.12) 0.3394 ≥50% Decrease 0.67 (0.52, 0.86) 0.0018 Hemorrhagic Stroke ≥0% Increase 1.00 <50% Decrease 0.84 (0.50, 1.40) 0.4716 ≥50% Decrease 1.04 (0.61, 1.78) 0.8864 0.4 0.7 1.0 1.3 1.6 1.9 2.2 Note: Percent change effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase Hazard Ratio (95% CI) Amarenco P, Goldstein LB, Szarek M, et al. Stroke. 2007;38:3198-3204

  39. Time Varying LDL-C and Stroke Risk HR (95% CI) p-value All Stroke ≥ 100 mg/dL 1.00 70 to < 100 mg/dL 1.01 (0.81, 1.27) 0.9076 < 70 mg/dL 0.72 (0.59, 0.89) 0.0016 0.4 0.7 1.0 1.3 1.6 1.9 2.2 Hazard Ratio (95% CI) Note: Nominal value effects from Cox proportional hazards models with adjustment for gender and baseline age with reference group = no change or increase 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. Mean Lipids and BP During Follow-up in Atorvastatin and Placebo Groups TG 150 125 LDL 100 75 Lipids (mg/dl) 50 140.0 HDL 25 139.5 SBP 139.0 138.5 0 0 3 6 12 18 24 30 36 42 48 54 60 66 72 LO 138.0 Time (months) 137.5 Blood Pressure (mm Hg) 137.0 82.0 81.5 81.0 80.5 DBP 80.0 1.0 0.0 0 3 6 12 18 24 30 36 42 48 54 60 66 72 LO Time (months) Solid lines = atorvastatin 80 mg group; dashed lines = placebo group Amarenco P, Goldstein LB, Messig M, et al. Stroke. 2009 LO = last observation

  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 No.subjects No (%)events HR 95% CI P-value OverallP-value* Stroke0 parameters 1 parameter 2 parameters 3 parameters 4 parameters Major cardiovascular events (MCVE) 0 parameter 1 parameters 2 parameters 3 parameters 4 parameters 662 1156 1926 906 80 662 1156 1926 906 80 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) 1.00 0.982 0.782 0.620 0.354 1.000 0.9030.7250.603 0.247 (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) 0.8859 0.0478 0.0018 0.0420 0.3704 0.0029 0.0001 0.0059 0.0012 <0.0001 1.0 0.0 0.5 1.5 *P value for differences between number of parameters achieved Amarenco P, et al. Stroke. 2009

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