cosmos

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



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)



PLAC-1

PLAC-1

LCAS-1REGRESS

CCAIT

CCAIT MARS MAAS

MARSREGRESS

MAASLCAS

2.180

2.6100

3.1120

3.6140

4.1160

4.7180

0

0.01

0.02

0.03

0.04

0.05

0.06

TreatmentPlacebo

?

LDL-C levels correlate with angiographic progression

MLDdecrease(mm/y)

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



IVUS coronary imaging

Rotating transducer Normal coronary anatomy

Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory



IVUS detects angiographically‘silent’ atheroma

IVUS=intravascular ultrasoundNissen S, Yock P. Circulation 2001; 103: 604–616

Angiogram IVUS

Little evidence of disease

Atheroma



Statin therapy can reduce atheroma area

EEM=external elastic membraneNissen SE et al. JAMA 2004; 291: 1071–1080



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



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



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)



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



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



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 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/CAGLipids/hsCRP

IVUS/CAGLipidshsCRP

LipidsLipids

LipidshsCRP

Lipids 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



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



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

126 Completed Study



n=126

年齢（歳） 62.6±7.7

男性（ % ） 76.2

BMI （ kg/m2 ） 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 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COSMOS：試驗開始時的患者背景



-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

p<0.0001

140.2

↓

82.9

47.1

↓

55.2

147.8

↓

130.3

3.12

↓

1.56

Baseline

↓

Follow up

變化率

（

平均

値

）

n=126

COSMOS lipid profiles



p=0.4673

p<0.0001

-10

-5

0

5

10

+7.25%

-5.07%

+0.76%

n=126

PlaqueVolume (mm3)

（％）

變化率

（

平均

値

）

Reduction of Plaque VolumeReduction of Plaque Volume

LumenVolume (mm3)

VesselVolume (mm3)

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.



* ： 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***

（％）

変化率

（

平均

値

）

-50

50

（ % ）

0

50HDL-CLDL-C

変化率

（

平均

値

）

LDL-C/HDL-Cratio

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收案之前已有或無使用降血脂藥治療者的 lipid profileslipid profiles以及以及 plaqueplaque體積變化體積變化

收案前已使用降血脂藥

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/day16.9±5.3 mg/day72.2% 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%



Baseline Follow-up (76wk)

LumenLumen LumenLumen

AtheromaAtheroma AtheromaAtheroma

COSMOS IVUS example

Case: 53 y/o woman RCA#2



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



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



LDL-C/HDL-C ratio

0 2 31

2

1

0

-1

-2

（ % ）

Cha

nge

of

PA

V

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 StudyLDL-C / HDL-C ratio

3.12 -> 1.56

cosmos

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