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COSMOS

COSMOS. CO ronary atherosclerosis S tudy M easuring effects O f rosuvastatin using intravascular ultrasound in Japanese S ubjects. Objective.

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COSMOS

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  1. COSMOS COronary atherosclerosis Study Measuring effects Of rosuvastatin using intravascular ultrasound in Japanese Subjects

  2. 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. LDL-C levels correlate withangiographic progression 0.06 PLAC-1 0.05 REGRESS LCAS-1 CCAIT 0.04 MLDdecrease(mm/y) PLAC-1 0.03 MARS MAAS CCAIT 0.02 MARS Treatment REGRESS Placebo LCAS 0.01 ? MAAS 0 2.1 80 3.1120 2.6100 4.1 160 4.7 180 3.6 140 LDL-C (mmol/L, mg/dL) LDL-C=low-density lipoprotein cholesterol; MLD=minimum lumen diameterr2=0.71; p=0.0005Adapted from Ballantyne CM et al. Curr Opin Lipidol 1997; 8: 354–361

  4. IVUS coronary imaging Rotating transducer Normal coronary anatomy Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory

  5. IVUS detects angiographically‘silent’ atheroma Angiogram IVUS Little evidence of disease Atheroma IVUS=intravascular ultrasoundNissen S, Yock P. Circulation 2001; 103: 604–616

  6. Statin therapy can reduce atheroma area EEM=external elastic membrane Nissen SE et al. JAMA 2004; 291: 1071–1080

  7. 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. 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. 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. 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 (HbA1c ≥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. 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. COSMOS – study design Rosuvastatin 2.5–20 mg 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 0 0 1 4 2 8 3 12 4 16 5 20 6 24 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 Lipids Eligibility Lipids hsCRP Lipids Lipids IVUS/CAG Lipids hsCRP Lipids IVUS/CAG Lipids/hsCRP Tolerability will be assessed at all visits 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

  13. COSMOS – 藥物投與方法 20mg/日 10mg/日 * 5mg/日 * 2.5mg/日 * * 觀察期（＜8週） 治療期（76週） *: The dose of rosuvastatin may be up-titrated to maximum of 20 mg/day to achieve target of 80mg/dL

  14. Patients flow 214 Subjects Enrolled 1 Did Not Receive Study Drug 213 Received ≧ 1Dose of Study Drug 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. COSMOS：試驗開始時的患者背景 n=126 平均値 平均値（±S.D.) 年齢（歳） 62.6±7.7 Analyzed coronary artery: vessel （%） 男性 （%） 76.2 vessel（%） BMI （kg/m2） 25.0±3.3 右冠動脈（RCA） 40.5 高血圧 （%） 76.2 左冠動脈前下行枝（LAD） 30.2 抽菸 （%） 28.6 左冠動脈回旋枝（LCX） 28.6 糖尿病 （%） 37.3 左冠動脈主幹部（LMT） 0.7 冠動脈疾病家族史 （%） 20.6 Analyzed coronary artery: segment （%） 低HDL-C血症 （%） 25.4 近側 26.2 不安定狹心症 （%） 7.9 遠側 31.7 其他 42.1 73.0 收案前已使用降血脂藥治療　（％） 試験終了時（76週）Rosuvastatin的投與量（mg/日） 16.9±5.3

  16. COSMOS lipid profiles LDL-C(mg/dL) HDL-C(mg/dL) TG(mg/dL) （％） LDL-C / HDL-C ratio 50 Baseline ↓ Follow up 140.2 ↓ 82.9 47.1 ↓ 55.2 3.12 ↓ 1.56 147.8 ↓ 130.3 變化率（平均値） +19.8% p<0.0001 0 -4.8% p=0.1639 -38.6% -47.5% p<0.0001 n=126 p<0.0001 -50

  17. Reduction of Plaque Volume （％） Lumen Volume (mm3) Vessel Volume (mm3) Plaque Volume (mm3) 10 5 +7.25% 變化率（平均値） p<0.0001 +0.76% 0 p=0.4673 -5.07% -5 • 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. p<0.0001 n=126 -10

  18. 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 （%） Plaque體積變化 LDL-C/HDL-C ratio 0 LDL-C HDL-C 50 50 開始時 ↓ 終了時 168.2 ↓ 78.8 129.8 ↓ 84.4 46.2 ↓ 53.7 47.4 ↓ 55.8 3.84 ↓ 1.53 2.85 ↓ 1.57 （％） p=0.6649 変化率（平均値） 変化率（平均値） -4.0* +18.3** +20.3** -5 0 -7.9* -33.5** p=0.1770*** -43.5** -10 -50 -52.5** *：p<0.02（相較於baseline）1-sample t-test -58.5** p<0.0001*** p<0.0001*** **：p<0.0001 (相較於baseline)1-sample t-test 收案前未使用降血脂藥 （－）：n=34 (27%) 收案前已使用降血脂藥 （＋）：n=92 (73%) ***2-sample t-test

  19. Prior use of lipid-lowering drugs: 73% • LDL-C: -33.5% • Prior without use of lipid-lowering drugs: 27% • LDL-C: -52.5% • 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)

  20. COSMOS IVUS example Follow-up (76wk) Baseline Case: 53 y/o woman RCA#2 Lumen Lumen Atheroma Atheroma

  21. Correlation between change in LDL-C/HDL-C ratio and change of plaque volume.

  22. Treatment with rosuvastatin 2.5 to 20 mg for 76 weeks was generally well tolerated

  23. 1 Relationship between Atherosclerosis&LH ratio To regress atherosclerosis in higher risk patients, an LH ratio ≦1.5 should be achieved （%） 2 1 Change of PAV progression 0 regression COSMOS Study LDL-C / HDL-C ratio 3.12 -> 1.56 -1 -2 1.5 0 2 3 LDL-C/HDL-C ratio Nicholls S.J. et al: JAMA. 2007; 297（5）：499-508

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