1. Cholesterol Lowering and CV Risk: Meta-analyses

2. On-Treatment LDL and CHD Events in Statin Trials 2 Adapted from Rosenson RS. Expert Opin Emerg Drugs. 2004;9:269-279. LaRosa JC et al. N Engl J Med. 2005;352:1425-1435. WOSCOPS - Rx 4S - Rx LIPID - Rx 4S - PBO CARE - Rx LIPID - PBO CARE - PBO WOSCOPS - PBO AFCAPS - PBO AFCAPS - Rx WOSCOPS - Rx 0 10 20 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Secondary Prevention Primary Prevention 200 (5.2) ASCOT - PBO ASCOT - Rx PROVE-IT - PRA PROVE-IT - ATV80 TNT - ATV10 Event rate (%) LDL-C achieved, mg/dL (mmol/L) 70 (1.8) HPS - PBO HPS - Rx TNT - ATV80

3. Second Cycle of the CTT Meta-analysis: Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction 0.50.7511.251.5 Relative risk (CI) per mmol/L LDL-C reduction Statin/more betterControl/less better Statin vs. control More vs. less statin First cycle (14 trials) A to Z PROVE-IT ALLIANCE ASPEN TNT 4D MEGA IDEAL SEARCH JUPITER GISSI-HF AURORA 5883 (3.1) 257 (7.2) 406 (11.3) 254 (5.4) 114 (2.7) 889 (4.0) 144 (9.0) 102 (0.5) 938 (5.2) 1347 (3.6) 105 (0.5) 172 (2.2) 362 (8.1) 7467 (4.0) 282 (8.1) 458 (13.1) 293 (6.4) 136 (3.3) 1164 (5.4) 162 (10.1) 140 (0.7) 1106 (6.3) 1406 (3.8) 194 (1.0) 174 (2.2) 368 (8.3) 0.78 (0.76 - 0.81) Subtotal (21 trials) 7136 (2.8)8934 (3.6) 0.79 (0.77 - 0.81) P < 0.001 Subtotal (5 trials) 3837 (4.5)4416 (5.3) 0.72 (0.66 - 0.78) P < 0.001 Total (26 trials)10973 (3.2)13350 (4.0) 0.78 (0.76 - 0.80) P < 0.001 Difference between more vs. less and statin vs. control: c 1 2 = 4.5, p=0.03 99% or95% CI No. of events (% pa) Statin/moreControl/less Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681. 3

4. Second Cycle of the CTT Meta-analysis: More vs Less Statin—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681. 4

5. Nonfatal MI CHD death Any major coronary event CABG PTCA Unspecified Any coronary revascularization Ischemic stroke Hemorrhagic stroke Unknown stroke Any stroke Any major vascular event (all 21 trials) 2310 (0.9%) 1242 (0.5%) 3380 (1.3%) 816 (0.3%) 601 (0.2%) 1686 (0.6%) 3103 (1.2%) 987 (0.4%) 188 (0.1%) 555 (0.2%) 1730 (0.7%) 7136 (2.8%) 3213 (1.2%) 1587 (0.6%) 4539 (1.7%) 1126 (0.4%) 775 (0.3%) 2165 (0.8%) 4066 (1.6%) 1225 (0.5%) 163 (0.1%) 629 (0.2%) 2017 (0.8%) 8934 (3.6%) 0.74 (0.69 - 0.78) 0.80 (0.73 - 0.86) 0.76 (0.73 - 0.79) P < 0.001 0.76 (0.69 - 0.83) 0.78 (0.69 - 0.89) 0.76 (0.70 - 0.83) 0.76 (0.73 - 0.80) P < 0.001 0.80 (0.73 - 0.88) 1.10 (0.86 - 1.42) 0.88 (0.76 - 1.02) 0.85 (0.80 - 0.90) P < 0.001 0.79 (0.77 - 0.81) P < 0.001 Second Cycle of the CTT Meta-analysis: Statin vs Control—Proportional Effects on Major Vascular Events Per Mmol/L LDL-C Reduction 5 No. of events (% pa) StatinControl Relative risk (CI) per mmol/L LDL-C reduction Statin betterControl better 99% or 95% CI Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681. 0.50.7511.251.5

6. Meta-analysis of Statin Trials and Fatal and Nonfatal Stroke 6 Amarenco P et al. Lancet Neurol. 2009;8:453-463. N = 165,732 Log-scale Study 0.1 Active group (%) Control group (%) RR (95% CI) Total: P < 0.0001 (heterogeneity: I 2 = 7.3%, P = 0.36) SEARCH JUPITER ASPEN MEGA IDEAL TNT ALLIANCE CARDS PROVE-IT A TO Z ASCOT-LLA ALLHAT-LLT GREACE HPS (with no prior CVD) PROSPER MIRACL GISSI AFCAPS/TexCAPS LIPID (with no prior CVD) Post-CABG CARE (with no prior CVD) WOSCOPS SSSS Sub-total: P < 0.0001 (heterogeneity: I 2 = 26.6%, P = 0.12) 4.2 0.4 2.8 1.3 3.4 2.3 2.9 1.5 1.0 1.2 1.7 4.0 1.2 3.2 4.7 0.8 0.9 0.4 3.3 2.6 1.9 1.4 2.5 4.6 0.7 3.2 1.6 3.9 3.1 3.2 2.8 0.9 1.6 2.4 4.5 2.1 4.8 4.5 1.6 0.9 0.5 3.9 2.4 2.8 1.5 3.5 SPARCL HPS (with prior CVD LIPID (with prior CVD) CARE (with prior CVD) Sub-total: P = 0.03 (heterogeneity: I 2 = 0.8%, P = 0.39) 11.2 10.3 9.5 13.5 13.1 10.4 13.3 20.0 Primary prevention of stroke 0.20.512510 0.91 (0.77, 1.08) 0.52 (0.34, 0.78) 0.89 (0.56, 1.40) 0.83 (057,1.20) 0.87 (0.70, 1.08) 0.76 (0.60, 0.96) 0.90 (0.58, 1.42) 0.53 (0.31, 0.90) 1.09 (0.59, 2.01) 0.79 (0.48, 1.29) 0.73 (0.56, 0.96) 0.91 (0.76, 1.09) 0.53 (0.24, 1.18) 0.67 (0.57, 0.77) 1.04 (0.82, 1.31) 0.50 (0.25, 1.00) 1.05 (0.56, 1.96) 0.82 (0.41, 1.67) 0.84 (0.67, 1.05) 1.12 (0.58, 2.18) 0.67 (0.44, 1.01) 0.90 (0.61, 1.34) 0.72 (0.51, 1.01) 0.81 (0.75, 0.87) Secondary prevention of stroke 0.82 (0.77, 0.87 0.85 (0.73, 0.99 0.99 (0.81, 1.21) 0.72 (0.46, 1.12) 0.68 (0.37, 1.25) 0.88 (0.78, 0.99) RR (95% CI)

7. Meta-analysis of Statin Trials and Stroke Mortality Amarenco P et al. Lancet Neurol. 2009;8:453-463. 7 SEARCH JUPITER CARDS ALLHAT-LLT GREACE HPS PROSPER MIRACL GISSI LIPID CARE WOSCOPS SSSS Sub-total: P = 0.18 (heterogeneity: I 2 = 0%, P = 0.48) Study Active group (%) Control group (%) RR (95% CI) Primary prevention of stroke 0.9 0.3 0.1 1.0 0.0 0.9 0.8 0.2 0.5 0.2 0.6 1.1 0.7 0.5 1.1 0.1 1.2 0.5 0.1 0.2 0.6 0.1 0.5 0.85 (0.60, 1.21) 0.50 (0.13, 2.00) 0.14 (0.02, 1.15) 0.95 (0.65, 1.38) 0.33 (0.01, 8.17) 0.81 (0.62, 1.05) 1.58 (0.81, 3.09) 1.51 (0.25, 9.02) 1.00 (0.25, 3.98) 0.81 (0.46, 1.43) 4.99 (0.58, 42.70) 1.50 (0.42, 5.30) 1.17 (0.54, 2.52) 0.90 (0.76, 1.05) RR (95% CI) Secondary prevention of stroke SPARCL Total: P = 0.10 (heterogeneity: I 2 = 8.1%, P = 0.36) 1.01.70.59 (0.36, 0.97) 0.87 (0.73, 1.03) 10.50.20.12510 Log-scale

8. Stroke Risk and LDL Lowering in Statin Trials 8 Each 1 mmol (39 mg) LDL-C reduction reduced the risk of stroke by 21% (95% CI, 6.3–33.5%; p<0.009) N = 165,732 Amarenco P et al. Lancet Neurol. 2009;8:453-463. 1.1 1.2 1.0 0.9 0.8 0.7 0.6 0.5 0.4 -15-10-20-30-35-25-40-45-50-55 Between Group Difference in LDL-Cholesterol Reduction, % (active minus control groups) Relative Risk of Stroke in Active vs Control Groups (non-log scale) LIPID TNT GISSI PROSPER PROVE-IT Post-CABG SPARCL-CS (-) SPARCL SPARCL-CS (+) WOSCOPS ASPEN ALLHAT-LLT SEARCH IDEAL ALLIANCE CARE CARDS GREACE JUPITER MIRACL MEGA A to Z AFCAPS/TexCAPS HPS ASCOT-LLA SSSS 0 0

9. Statin/more better Control/less better Vascular causes Nonvascular CHD Other cardiac All cardiac Ischemic stroke Hemorrhagic stroke Unknown stroke Stroke Other vascular Any vascular Cancer Respiratory Trauma Other nonvascular Any nonvascular Unknown death Any death 1887 (0.5%) 1446 (0.4%) 3333 (0.9%) 153 (0.0%) 102 (0.0%) 228 (0.1%) 483 (0.1%) 404 (0.1%) 4220 (1.2%) 1781 (0.5%) 224 (0.1%) 127 (0.0%) 811 (0.2%) 2943 (0.8%) 479 (0.1%) 7642 (2.1%) 2281 (0.6%) 1603 (0.4%) 3884 (1.1%) 139 (0.0%) 89 (0.0%) 273 (0.1%) 501 (0.1%) 409 (0.1%) 4794 (1.3%) 1798 (0.5%) 237 (0.1%) 127 (0.0%) 832 (0.2%) 2994 (0.8%) 539 (0.1%) 8327 (2.3%) 0.80 (0.74 - 0.87) 0.89 (0.81 - 0.98) 0.84 (0.80 - 0.88) 1.04 (0.77 - 1.41) 1.12 (0.77 - 1.62) 0.85 (0.66 - 1.08) 0.96 (0.84 - 1.09) 0.98 (0.81 - 1.18) 0.86 (0.82 - 0.90) 0.99 (0.91 - 1.09) 0.88 (0.70 - 1.11) 0.98 (0.70 - 1.38) 0.96 (0.83 - 1.10) 0.97 (0.92 - 1.03) 0.87 (0.76 - 0.99) 0.90 (0.87 - 0.93) Second Cycle of the CTT Meta-analysis: Proportional Effects on Cause-Specific Mortality Per Mmol/L LDL-C Reduction No. of deaths(% pa) Statin/moreControl/less Relative risk (CI) per mmol/L LDL-C reduction 99% or 95% CI Cholesterol Treatment Trialists Collaboration. Lancet. 2010;376:1670-1681. 0.50.7511.251.5 9

10. Meta-analysis of Statin Trials: Effect of Intensive LDL-C Lowering vs Standard Statin Therapy on Fatal and Nonfatal Stroke 10 Study SEARCH IDEAL TNT ALLIANCE PROVE-IT A to Z Total: P = 0.009 (heterogeneity: I 2 = 0%, P = 0.80) 4.2 3.4 2.3 2.9 1.0 1.2 4.6 3.9 3.1 3.2 0.9 1.6 Conventional arm (%) RR (95% CI) 0.91 (0.77, 1.08) 0.87 (0.70, 1.08) 0.76 (0.60, 0.96) 0.90 (0.58, 1.42) 1.09 (0.59, 2.01) 0.79 (0.48, 1.29) 0.87 (0.78, 0.96) 0.10.20.512510 Log-scale RR (95% CI) Amarenco P et al. Lancet Neurol. 2009;8:453-463. Intensive arm (%)