1. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 COSMOS COronary atherosclerosis Study Measuring effects Of rosuvastatin using intravascular ultrasound in Japanese Subjects

2. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Objective COSMOS will assess the effect of 76 weeks of treatment with rosuvastatin (CRESTOR™) 2.5–20 mg on the progression of atherosclerotic plaques in Japanese patients with CHD and hypercholesterolaemia Progression of plaque volume will be measured using intravascular ultrasound (IVUS)

3. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 PLAC-1 LCAS-1 REGRESS CCAIT MARSMAAS MARS REGRESS MAAS LCAS 2.1 80 2.6 100 3.1 120 3.6 140 4.1 160 4.7 180 0 0.01 0.02 0.03 0.04 0.05 0.06 Treatment Placebo ? LDL-C levels correlate with angiographic progression MLD decrease (mm/y) LDL-C (mmol/L, mg/dL) LDL-C=low-density lipoprotein cholesterol; MLD=minimum lumen diameter r 2 =0.71; p=0.0005 Adapted from Ballantyne CM et al. Curr Opin Lipidol 1997; 8: 354–361

4. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 IVUS coronary imaging Rotating transducerNormal coronary anatomy Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

5. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 IVUS detects angiographically ‘silent’ atheroma IVUS=intravascular ultrasound Nissen S, Yock P. Circulation 2001; 103: 604–616 Angiogram IVUS Little evidence of disease Atheroma

6. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Statin therapy can reduce atheroma area EEM=external elastic membrane Nissen SE et al. JAMA 2004; 291: 1071–1080

7. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Rationale IVUS is an accurate method of assessing the progression of atherosclerosis Evidence suggests that statin therapy may reduce atherosclerotic plaque volume as assessed by IVUS Large-scale multicentre studies are needed to assess the effect of statins on progression of plaque volume in patients with CHD and hypercholesterolaemia

8. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Study endpoints Primary Change (%) in plaque volume from baseline to end of rosuvastatin treatment (week 76) Secondary Change from baseline to week 76 in: – plaque volume in target lesion – plaque area, vascular cross-sectional lumen area, and total vascular area at same coronary artery cross-section where maximum plaque area found at baseline within target lesion of plaque volume – vascular lumen volume and total vascular volume in target lesion Change (%) from baseline in lipids, lipoproteins and hsCRP Safety

9. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Major inclusion criteria Men and women aged 20–75 years Inpatient or outpatient with CHD Planned to undergo CAG or PCI Hypercholesterolaemia: – statin-naïve: LDL-C ≥3.6 mmol/L (140 mg/dL) or TC ≥5.7 mmol/L (220 mg/dL) – statin-treated: LDL-C ≥2.6 mmol/L (100 mg/dL) or TC ≥4.7 mmol/L (180 mg/dL) Before PCI, ≥1 significant stenosis of ≥75% (candidate for PCI as defined by AHA) and ≥1 lesion of ≤50% stenosis (defined by AHA)

10. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Major exclusion criteria Acute MI 72 h before enrolment Heart failure of NYHA class III or above Serious arrhythmia Secondary hyperlipidaemia Familial hypercholesterolaemia (uncontrolled by statins) Uncontrolled hypertension (≥200/110 mmHg) Uncontrolled diabetes (HbA 1c ≥95%) Serum creatinine >177 µmol/L (2.0 mg/dL) Lesion requiring active intervention on CAG Obvious involvement of thrombosis in the lesion on CAG

11. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Data analysis Randomisation of 200 patients is required to enable detection of a mean reduction in plaque volume of 6.3% with 80% power at the one-sided significance level of 2.5% This allows for a 37% rate of post-randomisation withdrawals and unevaluable plaque area resulting from poor IVUS images Statistical analysis of the primary endpoint will be carried out on the per-protocol set using a mixed- effects model with observation time points as fixed effects and patients as random effects

12. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 COSMOS – study design Patients (n=214) 20–75 years Stable CAD, CHD, awaiting CAG/PCI Statin-naïve: LDL-C ≥3.6 mmol/L or TC ≥5.7 mmol/L Statin-treated: LDL-C ≥2.6 mmol/L or TC ≥4.7 mmol/L Visit: Week: –1 –8 Eligibility 0 Rosuvastatin 2.5–20 mg 7 28 8 32 9 36 10 40 11 44 12 48 13 52 14 56 15 60 16 64 17 68 18 72 19 76 6 24 5 20 4 16 3 12 2 8 1 4 IVUS/CAG Lipids/hsCRP IVUS/CAG Lipids hsCRP Lipids hsCRP Lipids CHD=coronary heart disease; CAG=coronary angiography; PCI=percutaneous coronary intervention; LDL-C=low-density lipoprotein cholesterol; TC=total cholesterol; IVUS=intravascular ultrasound; hsCRP=high-sensitivity C-reactive protein Tolerability will be assessed at all visits

13. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 觀察期（＜ 8 週） 治療期（ 76 週） * 2.5mg/ 日 5mg/ 日 * 10mg/ 日 * 20mg/ 日 * COSMOS – 藥物投與方法 *: The dose of rosuvastatin may be up-titrated to maximum of 20 mg/day to achieve target of 80mg/dL

14. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Patients flow 214 Subjects Enrolled 213 Received ≧ 1Dose of Study Drug 1 Did Not Receive Study Drug 87 Did Not Complete End Point Assessment 45 IVUS Not Analyzable 27 Lost to Follow-up 13 Withdrew Consent 2 Other 87 Did Not Complete End Point Assessment 45 IVUS Not Analyzable 27 Lost to Follow-up 13 Withdrew Consent 2 Other 126 Completed Study

15. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 n=126 年齢（歳） 62.6±7.7 男性 （ % ） 76.2 BMI （ kg/m 2 ） 25.0±3.3 高血圧 （ % ） 76.2 抽菸 （ % ） 28.6 糖尿病 （ % ） 37.3 冠動脈疾病家族史 （ % ） 20.6 低 HDL-C 血症 （ % ） 25.4 73.0 試験終了時（ 76 週） Rosuvastatin 的投與量（ mg/ 日） 16.9±5.3 平均値（ ±S.D.) 收案前已使用降血脂藥治療 （％） 不安定狹心症 （ % ） 7.9 vessel （ % ） 右冠動脈（ RCA ） 左冠動脈前下行枝（ LAD ） 左冠動脈回旋枝（ LCX ） 左冠動脈主幹部（ LMT ） Analyzed coronary artery: segment （ % ） 近側 26.2 遠側 31.7 其他其他 42.1 30.2 28.6 0.7 Analyzed coronary artery: vessel （ % ） 40.5 平均値 COSMOS ：試驗開始時的患者背景

16. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 -4.8% +19.8% -38.6% -47.5% -50 0 50 （％） TG (mg/dL) HDL-C (mg/dL) LDL-C (mg/dL) LDL-C / HDL-C ratio p<0.0001 p=0.1639 p<0.0001 140.2 ↓ 82.9 47.1 ↓ 55.2 147.8 ↓ 130.3 3.12 ↓ 1.56 Baseline ↓ Follow up n=126 COSMOS lipid profiles

17. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 p=0.4673 p<0.0001 -10 -5 0 5 10 +7.25% -5.07% +0.76% n=126 Plaque Volume (mm 3 ) （％） Reduction of Plaque Volume Lumen Volume (mm 3 ) Vessel Volume (mm 3 ) p<0.0001 Plaque volume was significantly reduced regardless of prior use of lipid-lowering drugs (P<0.02). Among all patients enrolled, 60% had net plaque regression.

18. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 * ： p<0.02 （相較於 baseline ） 1-sample t-test Plaque 體積變化 -10 -5 0 -7.9* -4.0* p=0.1770*** （％） -50 50 （%）（%） 0 HDL-CLDL-C LDL-C/HDL-C ratio p<0.0001*** -58.5** -43.5** p<0.0001*** -52.5** -33.5** p=0.6649 +18.3** +20.3** 收案前未使用降血脂藥 （－）： n=34 (27%) （＋）： n=92 (73%) 168.2 ↓ 78.8 47.4 ↓ 55.8 3.84 ↓ 1.53 開始時 ↓ 終了時 129.8 ↓ 84.4 46.2 ↓ 53.7 2.85 ↓ 1.57 ** ： p<0.0001 ( 相較於 baseline) 1-sample t-test ***2-sample t-test 收案之前已有或無使用降血脂藥治療者的 lipid profiles 以及 plaque 體積變化 收案前已使用降血脂藥

19. The COSMOS results showed significant plaque regression with CRESTOR:- Mean % change in Plaque Volume † : -5.1% (p<0.0001 vs baseline) Change from baseline in LDL-C: -38.6% (p<0.0001 vs baseline) Change from baseline in HDL-C: +19.8% (p<0.0001 vs baseline) The mean dosage of rosuvastatin at follow-up IVUS was ? 16.9±5.3 mg/day 72.2% received the maximum dosage (20 mg/day) Prior use of lipid-lowering drugs: 73% LDL-C: -33.5% Prior without use of lipid- lowering drugs: 27% LDL-C: -52.5%

20. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Baseline Follow-up (76wk)Lumen Lumen Atheroma Atheroma COSMOS IVUS example Case: 53 y/o woman RCA#2

21. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Correlation between change in LDL-C/HDL-C ratio and change of plaque volume.

22. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 Treatment with rosuvastatin 2.5 to 20 mg for 76 weeks was generally well tolerated

23. Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society AZT-CRES-10007 Jan-2010 LDL-C/HDL-C ratio 0 23 1 2 1 0 -2 （%）（%） Change of PAV 1.5 To regress atherosclerosis in higher risk patients, an LH ratio ≦ 1.5 should be achieved regression progression Relationship between Atherosclerosis & LH ratio Nicholls S.J. et al: JAMA. 2007; 297 （ 5 ）： 499-508 COSMOS Study LDL-C / HDL-C ratio 3.12 -> 1.56