Transcript LDL-C

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
LDL-C levels correlate with
angiographic progression
0.06
PLAC-1
0.05
LCAS-1
0.04
MLD
decrease
(mm/y)
REGRESS
PLAC-1
0.03
0.02
CCAIT
MARS
CCAIT
MARS
0.01
0
2.1
80
?
LCAS
2.6
100
MAAS
Treatment
Placebo
REGRESS
MAAS
3.1
120
3.6
140
4.1
160
LDL-C (mmol/L, mg/dL)
LDL-C=low-density lipoprotein cholesterol; MLD=minimum lumen diameter
r2=0.71; p=0.0005
Adapted 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
4.7
180
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
Angiogram
IVUS
Little
evidence of
disease
Atheroma
IVUS=intravascular ultrasound
Nissen S, Yock P. Circulation 2001; 103: 604–616
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
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 mixedeffects 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
Rosuvastatin 2.5–20 mg
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
Eligibility Lipids
IVUS/CAG
Lipids/hsCRP
2 3
4 5
6 7 8 9 10 11 12
8 12 16 20 24 28 32 36 40 44 48
Lipids
Lipids
hsCRP
13 14 15 16 17 18 19
52 56 60 64 68 72 76
Lipids
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
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
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
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
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
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
COSMOS：試驗開始時的患者背景
n=126
平均値（±S.D.)
年齢（歳）
62.6±7.7
男性 （%）
76.2
BMI （kg/m2）
25.0±3.3
平均値
Analyzed coronary artery: vessel （%）
vessel（%）
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
低HDL-C血症 （%）
25.4
近側
26.2
不安定狹心症 （%）
7.9
遠側
31.7
73.0
其他
42.1
收案前已使用降血脂藥治療 （％）
Analyzed coronary artery: segment （%）
試験終了時（76週）Rosuvastatin的
投與量（mg/日）
16.9±5.3
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
COSMOS lipid profiles
（％）
LDL-C
(mg/dL)
HDL-C
(mg/dL)
50
變
化
率
（
平
均
値
）
Baseline
↓
Follow up
140.2
↓
82.9
47.1
↓
55.2
LDL-C / HDL-C
ratio
TG
(mg/dL)
3.12
↓
1.56
147.8
↓
130.3
+19.8%
p<0.0001
0
-4.8%
p=0.1639
-38.6%
p<0.0001
n=126
-50
-47.5%
p<0.0001
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
Reduction of Plaque Volume
（％）
10
變 5
化
率
（
平 0
均
値
）
-5
-10
Plaque
Lumen
Vessel
Volume (mm3)
Volume (mm3)
Volume (mm3)
+7.25%
p<0.0001
+0.76%
p=0.4673
-5.07%
p<0.0001
n=126
•
•
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
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
0
Plaque體積變化
（%）
50
LDL-C
開始時
↓
終了時
168.2
↓
78.8
HDL-C
129.8
↓
84.4
（％）
変
化
率
（
平 -5
均
値
）
-4.0*
46.2
↓
53.7
47.4
↓
55.8
LDL-C/HDL-C
ratio
3.84
↓
1.53
2.85
↓
1.57
p=0.6649
変
化
率
（
平
均
値 0
）
+18.3** +20.3**
-7.9*
-33.5**
p=0.1770***
-10
-43.5**
-50
-52.5**
*：p<0.02（相較於baseline ）1-sample t-test
-58.5**
p<0.0001***
**：p<0.0001 (相較於baseline)
1-sample t-test
（－）：n=34 (27%)
收案前未使用降血脂藥
（＋）：n=92
***2-sample t-test
Reference: Circulation Journal
2009;(73%)
73(11): 2110-2117
收案前已使用降血脂藥
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
p<0.0001***
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%
• Prior without use of lipidlowering drugs: 27%
• LDL-C: -33.5%
• LDL-C: -52.5%
COSMOS IVUS example
Follow-up
Baseline
Lumen
Case: 53 y/o
woman RCA#2
Atheroma
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
(76wk)
Lumen
Atheroma
Correlation between change in LDL-C/HDL-C
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
Relationship between Atherosclerosis
（%）
2
&
LH ratio
To regress atherosclerosis in higher risk patients,
an LH ratio ≦1.5 should be achieved
1
progression
0
regression
COSMOS Study
LDL-C / HDL-C ratio
3.12 -> 1.56
-1
-2
0
1
1.5
2
LDL-C/HDL-C ratio
Nicholls S.J. et al: JAMA. 2007; 297（5）：499-508
Reference: Circulation Journal 2009; 73(11): 2110-2117
Circulation journal : official journal of the Japanese Circulation Society
AZT-CRES-10007
Jan-2010
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