1. SPARCL Stroke Prevention by Aggressive Reduction in Cholesterol Levels trial

2. SPARCL was designed to evaluate whether high-dose statin treatment reduces risk of stroke in patients with a recent stroke or TIA and no history of coronary heart disease SPARCL: Background and rationale Patients with prior stroke/TIA are at risk for future cardiovascular (CV) events Statins  stroke incidence in patients at risk for CV disease; however, stroke risk reduction with statin therapy has not been demonstrated in patients with a history of stroke or TIA SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-95. Heart Protection Study Collaborative Group. Lancet. 2004;363:757-67.

3. SPARCL: Study design SPARCL Investigators. N Engl J Med. 2006;355:549-59. Stroke or TIA in ≤6 months, no known CHD, LDL-C 100–190 mg/dL N = 4731 Atorvastatin 80 mg daily n = 2365 Placebo n = 2366 Randomized Double blind Primary end point: Fatal/nonfatal stroke Secondary end points: Major coronary or CV events Follow-up: ~5 years (until >540 primary end points)

4. SPARCL: Baseline characteristics Atorvastatin n = 2365 Placebo n = 2366 Male (%)6059 Age (years)63 Systolic BP (mm Hg)139138 Lipid profile (mg/dL) LDL-C133134 HDL-C50 Triglycerides144143 Risk factors (%) Hypertension6261 Diabetes17 Current smoker19 Former smoker4139 SPARCL Investigators. N Engl J Med. 2006;355:549-59.

5. SPARCL: Entry events AtorvastatinPlacebo n(%)n Entry event* Stroke Ischemic Hemorrhagic Other type or not determined 1655 1595 45 15 (70) (67) (2) (0.6) 1613 1559 48 6 (68) (66) (2) (0.3) TIA708(30)752(32) Unknown2(0.1)1(<0.1) *Ischemic stroke or TIA in >97% of patients SPARCL Investigators. N Engl J Med. 2006;355:549-59. N = 4731

6. SPARCL: Concomitant medications SPARCL Investigators. N Engl J Med. 2006;355:549-59. Atorvastatin n (%) Placebo n (%) Concomitant therapy Antiplatelet agent2067 (87)2063 (87) ACE inhibitor683 (29)667 (28) Dihydropyridine derivative350 (15)359 (15) β-blocker414 (18)422 (18) ARB110 (5)102 (4) Vitamin K antagonist, including warfarin139 (6)154 (7) Prior statin therapy57 (2)63 (3) N = 4731

7. Time since randomization (years) SPARCL: High-dose statin treatment reduces fatal/nonfatal stroke *Adjusted SPARCL Investigators. N Engl J Med. 2006;355:549-59. Fatal/ nonfatal stroke (%) 0 0123456 16 12 8 4 16% RRR* HR 0.84 (0.71–0.99) P = 0.03 Placebo Atorvastatin NNT = 46 patients for 5 years Primary outcome

8. SPARCL: Treatment effect on stroke and TIA Hazard ratio SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Adjusted HR* (95% CI) 0.84 (0.71–0.99) 0.57 (0.35–0.95) 0.87 (0.73–1.03) 0.77 (0.67–0.88) 0.74 (0.60–0.91) Primary outcome Stroke (total) Fatal Nonfatal Secondary outcomes Stroke or TIA TIA P 0.03 0.11 <0.001 0.004 0.31.01.7 N = 4731 Aggressive statin therapy BetterWorse

9. SPARCL: High-dose statin reduces major coronary events and stroke SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest, and stroke 0 0 30 20 10 123456 Time since randomization (years) Major CV events* (%) 20% RRR HR 0.80 (0.69–0.92) P = 0.002 Placebo Atorvastatin NNT = 29 patients for 5 years

10. SPARCL: Reductions in major coronary events SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest 0 0 10 6 2 123456 Time since randomization (years) Major coronary events* (%) 35% RRR HR 0.65 (0.49–0.87) P = 0.003 Placebo Atorvastatin 8 4

11. SPARCL: Adverse events SPARCL Investigators. N Engl J Med. 2006;355:549-59. Atorvastatin Placebo n(%)n Musculoskeletal AE Myalgia129(5.5)141 (6.0) Myopathy7(0.3)7 Rhabdomyolysis2(0.1)3 ALT or AST >3x ULN51(2.2)11(0.5) Creatine kinase >10x ULN2(0.1)0 N = 4731

12. SPARCL: Summary Atorvastatin 80 mg yielded: Primary end point  16% fatal/nonfatal stroke (P = 0.03) Significant benefit despite small  hemorrhagic stroke with atorvastatin (2.3%) vs placebo (1.4%) Secondary end points  35% major coronary events (P = 0.003)  20% major CV events (P = 0.002)  42% any coronary events (P < 0.001)  26% any CV events (P < 0.001)  45% revascularizations (P < 0.001) SPARCL Investigators. N Engl J Med. 2006;355:549-59.

13. SPARCL: Implications Aggressive statin therapy should be strongly considered soon after stroke or TIA Magnitude of benefit may vary depending on baseline stroke subtype SPARCL results support the concept of stroke or TIA as a CHD risk equivalent SPARCL Investigators. N Engl J Med. 2006;355:549-59.