The SPARCL trial investigated whether high-dose atorvastatin (80 mg daily) could reduce the risk of fatal or non-fatal stroke in patients who had a stroke or transient ischemic attack 1-6 months prior and no history of coronary heart disease. The double-blind randomized controlled trial assigned 4731 eligible patients to atorvastatin or placebo groups. After a median follow-up of 4.9 years, treatment with atorvastatin reduced the risk of fatal or non-fatal stroke by 2% compared to placebo, with a number needed to treat of 53. Atorvastatin also reduced the risk of major cardiovascular events by 18% compared to placebo.

1. SPARCL TRIAL: HIGH-DOSE ATORVASTATIN AFTER STROKE OR TRANSIENT ISCHEMIC ATTACK PRESENTED BY: TING CHUONG WEI KENNY GOH WEI CHUAN CHEN SIAW MING 12-12-2007

2. Atherosclerosis Timeline Phase I: Initiation LDL-C plays a major role in initiating the development of atherosclerotic plaque. Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine . 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med . 2000;247:349-358. Media Intima Phase II: Progression Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly. LDL-C Lumen Unstable Stable Phase III: Complication Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.

3. Mechanism of Action of Statins Cholesterol Synthesis Pathway acetyl CoA HMG-CoA mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene cholesterol dolichols ubiquinones HMG-CoA synthase HMG-CoA reductase Squalene synthase Statins X

5. Percentage Reduction of LDL-C by Statin Change in LDL-C from baseline (%) 0 – 10 – 20 – 30 – 40 – 50 – 60 – 5 – 15 – 25 – 35 – 45 – 55 10 mg 20 mg 80 mg 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg Atorvastatin Pravastatin 40 mg Drug Information Handbook 13 th Edition 20 mg 40 mg 80 mg Lovastatin Simvastatin

10. 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 Median follow-up: ~ 4.9 years

14. QS2: WAS THIS RANDOMIZED CONTROL-TRIAL AND WAS IT APPROPRIATE? YES, this trial is a Randomized Control-Trial (RCT) to study the comparison of risk reduction incidence of fatal and non-fatal stroke among the patients receiving 80 mg of atorvastatin per day with placebo over median follow up 4.9 years . This RCT is an appropriate research design because this is a clinical question and is the most reliable form of scientific event. SPARCL Investigators. N Engl J Med. 2006;355:549-59.

18. Table 1: Baseline characteristics of patients SPARCL Investigators. N Engl J Med. 2006;355:549-59. 17 17 Diabetes 61 62 Hypertension 39 41 Former smoker 19 19 Current smoker Risk factors (%) 143 144 Triglycerides 50 50 HDL-C 134 133 LDL-C Lipid profile (mg/dL) 138 139 Systolic BP (mm Hg) 63 63 Age (years) 59 60 Male (%) Placebo n = 2366 Atorvastatin n = 2365

19. Table 2: Entry events *Ischemic stroke or TIA in >97% of patients N = 4731 SPARCL Investigators. N Engl J Med. 2006;355:549-59. (<0.1 ) 1 (0.1) 2 Unknown (32) 752 (30) 708 TIA (68) (66) (2) (0.3) 1613 1559 48 6 (70) (67) (2) (0. 6 ) 1655 1595 45 15 Entry event* Stroke Ischemic Hemorrhagic Other type or not determined (%) n (%) n Placebo Atorvastatin

20. Table 3: Concomitant medications N = 4731 SPARCL Investigators. N Engl J Med. 2006;355:549-59. 154 (7) 139 (6) Vitamin K antagonist, including warfarin BACK 63 (3) 57 (2) Prior statin therapy 102 (4) 110 (5) ARB 422 (18) 414 (18) β -blocker 359 (15) 350 (15) Dihydropyridine derivative 667 (28) 683 (29) ACE inhibitor 2063 (87) 2067 (87) Antiplatelet agent Concomitant therapy Placebo n (%) Atorvastatin n (%)

30. Time since randomization (years) High-dose statin treatment reduces fatal/nonfatal stroke SPARCL Investigators. N Engl J Med. 2006;355:549-59. Fatal/ nonfatal stroke (%) 0 0 1 2 3 4 5 6 16 12 8 4 14.5% RRR HR 0.84 (0.71–0.99) P = 0.03 Placebo Atorvastatin NNT = 53 patients for median f/u 4.9 years Primary outcome

31. Secondary outcomes: 24 4.2 20.1 15.9 1. Stroke or TIA 44 2.3 8.8 6.5 a. TIA The result is statically not significant (P = 0.98) 6.6 2.9 3.4 2.1 3.1 1.7 ARR (%) - 15 34 29 48 33 59 NNT 8.9 9.1 8. Death 29.0 22.4 7. Any CVS event 6.9 4.0 6. Revascularization 8.6 5.2 5. Any coronary events 6.4 4.3 4. Acute coronary events 17.2 14.1 3. Major CVS event 5.1 3.4 2. Major coronary events CER (%) EER (%) Outcomes

32. High-dose statin reduces major cardiovascular events SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest, and stroke 0 0 30 20 10 1 2 3 4 5 6 Time since randomization (years) Major CVS events* (%) 18% RRR HR 0.80 (0.69–0.92) P = 0.002 Placebo Atorvastatin NNT = 33 patients for median 4.9 years

33. 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 1 2 3 4 5 6 Time since randomization (years) Major coronary events* (%) 33% RRR HR 0.65 (0.49–0.87) P = 0.003 Placebo Atorvastatin 8 4

36. SAFETY ASSESSMENT: ADVERSE EVENTS SPARCL Investigators. N Engl J Med. 2006;355:549-59. N = 4731 0 11 3 7 141 n Placebo Atorvastatin 2 51 2 7 129 n (0.5) (2.2) ALT or AST > 3x ULN (0.1) Creatine kinase >10x ULN (6.0) (5.5) Myalgia (0.3) (0.3) Myopathy (0.1) (0.1) Rhabdomyolysis Musculoskeletal AE (%) (%)

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