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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
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)
Reference: Circulation Journal 2009; 73(11): 2110-2117 Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007 Jan-2010
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
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 transducer Normal coronary anatomy
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
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 ultrasoundNissen S, Yock P. Circulation 2001; 103: 604–616
Angiogram IVUS
Little evidence of disease
Atheroma
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 membraneNissen SE et al. JAMA 2004; 291: 1071–1080
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
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
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)
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 (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
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
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 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
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
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
126 Completed Study
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/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
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
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
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
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.
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***
(%)
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%
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)
LumenLumen LumenLumen
AtheromaAtheroma AtheromaAtheroma
COSMOS IVUS example
Case: 53 y/o woman RCA#2
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 Correlation between change in LDL-C/HDL-C ratio and change of plaque volume. ratio and change of plaque volume.
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
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 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