Transcript Document

ASTEROID
A Study to Evaluate the Effect of
Rosuvastatin on Intravascular
Ultrasound-Derived Coronary
Atheroma Burden
References
Nissen et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID
trial. JAMA 2006;295(13):1556-65.
Ballantyne et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary
angiography in ASTEROID. Circulation 2008;in press.
ASTEROID
•
Use of intravascular ultrasound (IVUS) and
quantitative coronary angiography (QCA) to
evaluate the effect of rosuvastatin on
atherosclerotic disease in patients with
coronary artery disease (CAD)
IVUS Coronary Imaging Technique
Rotating transducer
Normal coronary anatomy
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
The IVUS Technique Can Detect
Angiographically “Silent” Atheroma
Angiogram
No evidence
of disease
IVUS
Little
evidence of
disease
Atheroma
Nissen S, Yock P. Circulation 2001;103:604–16.
Rationale
• Angiographic studies indicate that substantial LDL-C
reductions (≥40%) are needed to slow progression of
arterial stenosis
• Although QCA has been used to measure luminal
narrowing, it may underestimate atherosclerotic burden
• IVUS enables measurement of the volume of atheroma
within the wall of the arteries by combining a series of
cross-sectional images of the vessel over a predefined
length
• IVUS has emerged as the most sensitive measure of the
progression of coronary disease and an appropriate
method to assess the effects of intensive lipid lowering on
progression/regression of atherosclerosis
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Objectives
• The primary objective of ASTEROID was to evaluate
whether long-term treatment with rosuvastatin 40 mg in
CAD patients resulted in regression of coronary artery
atheroma burden, as assessed by the percentage atheroma
volume (PAV) in the entire segment length of the artery
assessed, and total atheroma volume (TAV) in the most
severely diseased segment, as measured by IVUS
• Secondary objectives included to determine whether longterm treatment with rosuvastatin 40 mg results in
regression of (i) coronary atheroma burden, as assessed by
TAV in the total segment as measured by IVUS and (ii)
CAD, as measured by QCA
Adapted from Nissen et al. JAMA 2006;295(13):1556-65, Ballantyne et al. Circulation 2008;in press.
ASTEROID: Study Design
Patients (≥18 years)
CAD, undergoing coronary
angiography
Target coronary artery: ≤50%
reduction in lumen diameter of
≥40 mm segment
Rosuvastatin 40 mg (n=349 for IVUS analysis;
n=292 for QCA analysis)
Target segment for QCA: all
segments >25% at baseline
No cholesterol entry criteria
Visit:
Week:
2
0
1
–6
IVUS
QCA
Lipids
Eligibility
assessment
Lipids
3
13
4
26
5
39
6
52
7
65
8
78
9
91
10
104
Lipids Tolerability
Lipids
Tolerability Tolerability IVUS
QCA
Tolerability
Tolerability
Lipids
Tolerability
Study End Points
• Dual primary end points:
– Change in PAV in the entire segment of coronary artery assessed by
IVUS
– Change in TAV in the most severely diseased 10-mm segment of the
coronary artery assessed by IVUS
• Secondary end points:
– Change in TAV within the entire segment assessed by IVUS
– Change in per cent diameter stenosis (%DS) for all lesions with >25%
stenosis severity as measured by QCA
– Change in the minimal lumen diameter (MLD) within all measured
coronary segments as measured by QCA
– Percentage change from baseline in lipid and lipoprotein levels
– Tolerability
Adapted from Nissen et al. JAMA 2006;295(13):1556-65, Ballantyne et al. Circulation 2008;in press.
ASTEROID
IVUS Analysis
IVUS Determination of Atheroma Area
Precise planimetry of EEM and lumen borders
allows calculation of atheroma cross-sectional area
EEM Area
Lumen
Area
(EEM area — Lumen Area)
Images courtesy of Cleveland Clinic Intravascular Ultrasound Core Laboratory
EEM=external elastic membrane
IVUS Efficacy Measures
EEM Area
Change
in Per Cent
Atheroma
Volume
Lumen
Area
(EEM – Lumen)CSA
(EEM – Lumen)CSA
=
n
X 100 –

X 100
n
EEMCSA
EEMCSA
(Month 24)
(Baseline)
(EEM – Lumen)
Most diseased
contiguous
10 cross-sections
Normalized*
Total
Atheroma
Volume
 (EEMCSA - LumenCSA)
=
Number cross-sections
in patient’s pullback
x
Median number crosssections for all patients
*Normalized = adjusting for pullbacks of differing lengths thereby resulting in an equal weighting
of each individual patient
Major Inclusion Criteria
 Patients requiring coronary angiography for a clinical
indication
 Angiographic evidence of CAD
– Entire coronary circulation: ≥1 lesion with >20% reduction in
lumen diameter in any coronary artery
– Target coronary artery for IVUS: ≤50% reduction in lumen
diameter throughout a target segment with a minimum
length of 40 mm
– Target segment for QCA: all segments >25% at baseline
– No cholesterol entry criteria
 Men or women aged ≥18 years, statin-naïve
Adapted from Nissen et al. JAMA 2006;295(13):1556-65, Ballantyne et al. Circulation 2008;in press.
Major Exclusion Criteria
 Statin-naïve requirement: treatment with lipid-lowering
therapy for not more than 3 months within the last 12
months
 NYHA Class III or IV congestive heart failure, LVEF <0.35,
recent coronary bypass surgery or clinically significant
heart disease likely to require surgical intervention
 Active liver disease or hepatic dysfunction (ALT, AST or
bilirubin ≥1.5 x ULN)
 Uncontrolled triglyceride levels (≥500 mg/dL [5.7 mmol/L])
 Uncontrolled diabetes mellitus (HbA1c ≥10%)
 Uncontrolled hypertension (≥200/100 mm Hg)
 CK >3 x ULN
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Baseline Characteristics
 Mean age of patients was 58.5 years
 70% of patients were male
 97% were white
 Median body mass index was 28.4
 96% of patients had a history of hypertension
 13% of patients had a history of diabetes
 17% of patients had a history of acute coronary syndrome
 25% of patients had history of myocardial infarction
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Concomitant Medications
 84% of patients were taking ASA
 53% of patients were taking ACE inhibitors
 18% of patients were taking angiotensin receptor blockers
 85% of patients were taking organic nitrates
 84% of patients were taking beta-blockers
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Mean Baseline Lipid Levels
N=346
Baseline level
(mg/dL)
Baseline level
(mmol/L)
LDL-C
130.4
3.4
TC
204.0
5.3
TG
152.2
1.7
43.1
1.1
HDL-C
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
End Point Analysis:
Change in Median PAV
Median PAV
Change from baseline (%)
0
-0.1
n=349
-0.2
-0.3
-0.4
-0.5
-0.6
-0.7
-0.8
-0.9
- 0.79%
*
*P<0.001 for difference from baseline values.
Wilcoxon signed rank test
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
End Point Analysis:
Change in Key IVUS Parameters
Change from baseline (%)
Median atheroma volume in the
most diseased 10-mm
subsegment
0
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
n=319
Median normalized TAV
n=346
- 6.8%
*
- 9.1%
*
*P<0.001 for difference from baseline. Wilcoxon signed rank test
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Number (%) of Patients Showing Regression
Measured by Each IVUS Parameter
78%
Normalized TAV
IVUS
parameter
measured
78%
Atheroma volume in the most diseased 10-mm subsegment
64%
PAV
0
10
20
30
40
50
60
70
80
Percentage of patients showing regression
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
90
100
Example of Regression of Atherosclerosis with
Rosuvastatin in ASTEROID (measured by IVUS)
Sipahi I, Nicholls S, Tuzcu E,
Nissen S. Interpreting the
ASTEROID trial: Coronary
atherosclerosis can regress with
very intensive statin therapy.
Cleve Clin J Med, 2006; 73:937944.
Reprinted with
permission. Copyright
2006. Cleveland Clinic
Foundation. All rights reserved.
Median change from baseline (%)
Percentage Change** in LDL-C, HDL-C, TC
& LDL-C/HDL-C Ratio
30
LDL-C
20
10
0
-10
HDL-C
*
15%
TC
LDL-C/HDL-C
n=346
n=346
n=346
n=346
-20
-30
- 34%
*
-40
-50
-60
- 53%
*
*P<0.001
**From
time-weighted average throughout the duration of therapy
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
- 59%
*
Change in Per Cent Diameter Stenosis vs.
On-Treatment LDL-C in QCA Trials
1.4
Placebo
1.2
Statin
CCAIT
PLAC I
MARS
MAAS
LCAS
1
0.8
MARS
0.6
CCAIT
PLAC I
0.4
0.2
LCAS
0
-0.2
-0.4
-0.6
40
60
80
100
MAAS
120
140
160
180
On-treatment LDL-C (mg/dL)
ASTEROID
-0.8
-1
ASTEROID - rosuvastatin; MAAS - simvastatin; CCAIT - lovastatin; MARS – lovastatin; LCAS fluvastatin; PLAC I - pravastatin
Adapted from Ballantyne et al. Circulation 2008; in press.
Median change from baseline (%)
Percentage Change** in Other
Lipids and Lipoproteins
30
non-HDL-C
TG
ApoB
20
ApoB/ApoA1
*
9%
10
0
ApoA1
n=346
n=346
n=346
n=346
n=346
-10
-20
- 15%
*
-30
-40
-50
-60
- 47%
*
- 42%
*
TG=triglycerides
*P<0.001
**From time-weighted average throughout the duration of therapy
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
- 46%
*
Change in PAV by Pre-specified Subgroups:
Demographic Characteristics
Median change from baseline (%)
0
Age ≤
median
(n=180)
Age >
median
(n=169)
Male
(n=245)
BMI ≤
median
Female
(n=104) (n=174)
BMI >
median
(n=173)
History of
diabetes
(n=46)
No history
of diabetes
(n=303)
-0.2
-0.4
-0.6
-0.8
-1
-0.6%
*
-0.8%
-0.8%
*
*
-0.7%
-0.7%
*
*
-0.8%
-0.9%
-0.9%
*
*
*Wilcoxon signed rank test for comparisons to baseline
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
*
Change in PAV by Pre-specified Subgroups –
Average On-Treatment LDL-C
Median change from baseline (%)
0
LDL-C ≤
mean
(n=192)
LDL-C >
mean
(n=157)
LDL-C <
1.81 mmol/L
(n=254)
LDL-C 1.8-2.6
mmol/L
(n=78)
-0.2
2.6 mmol/L
(n=17)
-0.2%
-0.3%
-0.4
-0.6
-0.6%
*
-0.8
-0.9%
-1
-1.2
LDL-C >
*
-1.1%
*
*Wilcoxon signed rank test for comparisons to baseline
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Median change from baseline (%)
Change in PAV by Pre-specified Subgroups:
Average On-treatment HDL-C
0
HDL-C ≤
mean
(n=197)
HDL-C >
mean
(n=152)
HDL-C >
1.1mmol/L
(n=205)
HDL-C ≤
HDL-C <
HDL-C >
1.1mmol/L 1.1mmol/L 1.1 mmol/L
(n=144)
(n=80)
(n=269)
HDL-C <
0.9 mmol/L
(n=34)
HDL-C >
0.9 mmol/L
(n=315)
-0.2
-0.4
-0.6
-0.7%
-0.8
-1
-1.2
-0.9%
*
*
-0.7%
*
-0.8%
-0.7%
-0.7%
*
*
*
-1.4
-1.3%
-1.6
*
-1.5%
*
*Wilcoxon signed rank test for comparisons to baseline
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
Summary: IVUS Results
 ASTEROID showed that in patients with CAD, regression of
coronary atherosclerosis can be achieved with intensive statin
therapy using rosuvastatin 40 mg
 Rosuvastatin 40 mg produced significant regression of
atherosclerosis for all three IVUS measures assessed
 Regression occurred in 4 out of 5 patients and in virtually all
subgroups evaluated, including men and women, older and
younger patients and in most subgroups defined by lipid levels
 Regression of atherosclerosis was associated with a substantial
reduction of LDL-C (-53%) combined with a significant increase
in HDL-C (+15%)
 Analysis of results from ASTEROID and other previously
conducted IVUS trials confirms the strong correlation between
LDL-C reduction and reduction in atheroma volume
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
ASTEROID
QCA Analysis
ASTEROID: QCA Analysis
 The effect of rosuvastatin on coronary stenoses by QCA
was a secondary end point in ASTEROID
 507 patients with coronary disease received
rosuvastatin 40 mg for 24 months
 Blinded QCA analyses of %DS and MLD was performed
for up to 10 segments of coronary arteries and major
branches with >25% diameter stenosis at baseline
 379 patients had baseline and follow-up angiography
 292 patients had 1 or more segments with >25%
stenosis at baseline
Adapted from Ballantyne et al. Circulation 2008;in press.
ASTEROID: QCA Analysis
• By providing lumen
information
throughout the
coronary tree, QCA
provides a more
“global measure” of
coronary atheroma
and complements the
detailed imaging data
provided by IVUS for
larger vessels
ASTEROID: QCA Efficacy Measures
 Change from baseline in %DS for all lesions with >25%
stenosis severity
 Change from baseline in the MLD within all measured coronary
segments
%DS =
Reference diameter - MLD
Reference diameter
X 100
Percentage Change* in LDL-C, HDL-C, TC
& LDL-C/HDL-C Ratio
Mean change from baseline (%)
LDL-C
#On-treatment
therapy
20
HDL-C
TC
LDL-C/HDL-C
13.8%
10
0
n=292
n=292
n=292
n=292
-10
-20
-30
- 34%
-40
-50
-60
- 53%
- 58%
-70
and per cent change from baseline were based on time-weighted average throughout the duration of
Adapted from Ballantyne et al. Circulation 2008;in press.
QCA Results
Baseline change in %DS during treatment, analyzed
by patient
%DS
(n=292)
Mean
(SD)
Median
(range)
Baseline
37.3%
(8.4)
35.7%
(26.0-73.0)
End of
study
36.0%
34.5%
(10.1)
(8.0-74.0)
Mean
change from
baseline (SD)
Median change
from baseline
(Q1 to Q3)
-1.3%
-0.50%
(8.00)
(-4.0-2.0)
P<0.001*
*Wilcoxon signed rank test
Q1=25th percentile; Q3=75th percentile
Adapted from Ballantyne et al. Circulation 2008;in press
QCA Results
Baseline and Change in MLD During Treatment,
Analyzed by Patient
MLD
(n=281)
Mean
(SD)
Median
(range)
Baseline
1.65 mm
1.62 mm
End of
study
1.68 mm
1.67 mm
(0.36)
(0.38)
Mean
change from
baseline (SD)
Median change
from baseline
(Q1 to Q3)
+0.03 mm
+0.02 mm
(0.56-2.65)
(0.76-2.77)
(0.20)
(-0.04-0.11)
P<0.001*
*Wilcoxon signed rank test
Q1=25th percentile; Q3=75th percentile
Adapted from Ballantyne et al. Circulation 2008;in press.
QCA Results
Progression vs. regression in per cent diameter
stenosis analyzed by patient
Stenosis reduced (regression)
No change
Stenosis increased (progression)
Stenosis reduced by >10% (regression)
Stenosis changed by <10%
Stenosis increased by >10% (progression)
Adapted from Ballantyne et al. Circulation 2008;in press.
Total
(N=292)
Per cent of
total
156
53.4%
17
5.8%
119
40.8%
22
7.5%
261
89.4%
9
3.1%
QCA Results
Progression vs. regression of MLD during treatment
analyzed by patient
MLD larger (regression)
No change
MLD smaller (progression)
MLD larger by >0.2 mm (regression)
Change <0.2 mm
MLD smaller by >0.2 mm (progression)
Adapted from Ballantyne et al. Circulation 2008;in press.
Total
(N=281)
Per cent of
total
155
55.2%
12
4.3%
114
40.6%
34
12.1%
230
81.9%
17
6.0%
Change in Progression of IVUS PAV Volume vs.
LDL-C in IVUS Trials
2
REVERSAL
Change in PAV (%)
1.5
CAMELOT
pravastatin
placebo
1
ACTIVATE
placebo
0.5
A-Plus
REVERSAL
placebo
atorvastatin
0
50
-0.5
-1
60
70
80
90
100
110
Mean LDL-C (mg/dL)
ASTEROID
rosuvastatin
On-treatment LDL-C (mg/dL)
Adapted from JAMA 2006;295:1556-65, Cleve Clin J Med 2006;73:937-44.
r2=0.95
P<0.001
120
Change in % stenosis/year
Relationship Between On-treatment LDL-C and % Change in LDL-C
and Change in %DS and MLD in Statin Angiography Studies
1.4
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
-0.4
-0.6
-0.8
-1
CCAIT
PLAC I
LCAS
MARS
CCAIT
PLAC I
LCAS
40
60
CCAIT
MARS
PLAC I
MARS
MAAS
LCAS
MAAS
CCAIT
MARS
PLAC I
MAAS
MAAS
80 100 120 140 160 180
On-treatment LDL-C (mg/dL)
-70 -60
-50
LCAS
-40 -30 -20 -10
0
Per cent change in LDL-C
10
ASTEROID
ASTEROID
Change in MLD (mm/year)
-0.06
-0.04
LCAS
PLAC I
CCAIT
-0.02
MARS
0
0.02
LCAS
40
60
PLAC I
CCAIT
PLAC I
CCAIT
REGRESS
MAAS
MARS
PLAC I
CCAIT
REGRESS
MAAS
80 100 120 140 160 180
On-treatment LDL-C (mg/dL)
ASTEROID
0.04
Adapted from Ballantyne et al. Circulation 2008;in press.
MARS
-70 -60
-50
ASTEROID
-40
REGRESS
LCAS
MAAS
MARS
REGRESS
LCAS
MAAS
-30
-20
-10
0
Per cent change in LDL-C
10
Change in Per Cent Diameter Stenosis vs.
On-treatment HDL-C in QCA Trials
CCAIT
1.4
1.2
1
0.8
0.6
PLAC I
MAAS
Placebo
LCAS
MARS
CCAIT
PLAC I
MARS
0.4
0.2
0
40
-0.2
-0.4
Statin
MAAS
LCAS
45
50
On-treatment HDL-C (mg/dL)
-0.6
-0.8
-1
Adapted from Ballantyne et al. Circulation 2008;in press.
ASTEROID
Change in % stenosis/year
Relationship Between On-treatment HDL-C and % Change in HDL-C
and Change in %DS and MLD in Statin Angiography Studies
CCAIT
1.4
1.2
PLAC I
LCAS
MARS
1
MAAS
0.8
CCAIT
MARS
0.6
PLAC I
0.4
LCAS
MAAS
0.2
0
45
-0.2 40
On-treatment HDL-C (mg/dL)
-0.4
-0.6
ASTEROID
-0.8
-1
CCAIT
LCAS
PLAC I
MAAS
MARS
CCAIT
MARS
PLAC I
LCAS
MAAS
50
-5
0
5
Per cent change in HDL-C
10
15
20
ASTEROID
Change in MLD (mm/year)
-0.06
REGRESS
-0.04
-0.02
REGRESS
0
0.02
35
PLAC I
CCAIT
LCAS
MAAS
PLAC I
MARS
CCAIT
MARS
MAAS
LCAS
40
45
On-treatment HDL-C (mg/dL)
REGRESS
MAAS
MARS
PLAC I
CCAIT
LCAS
PLAC I
CCAIT
MARS
MAAS
50
ASTEROID
0.04
Adapted from Ballantyne et al. Circulation 2008;in press.
55
-5
0
5
REGRESS
LCAS
10
Per cent Change in HDL-C
15
ASTEROID
20
Summary: QCA results
 ASTEROID QCA analysis showed that in patients with CAD,
regression of coronary atherosclerosis can be achieved with
intensive therapy using rosuvastatin 40 mg
 Rosuvastatin 40 mg produced significant regression of
atherosclerosis in terms of both reducing %DS and increasing
MLD
 This regression of atherosclerosis was associated with a
substantial reduction of LDL-C (-53%) to 61 mg/dL (1.58
mmol/L) together with a significant increase in HDL-C
(+13.8%) to 48.3 mg/dL (1.25 mmol/L).
 An analysis of the ASTEROID QCA results and previous statin
angiographic trials shows a similar association between the
change in %DS and change in MLD with on-treatment and per
cent change for both LDL-C and HDL-C
Adapted from Ballantyne et al. Circulation 2008;in press.
Tolerability
 In ASTEROID, rosuvastatin 40 mg was taken by more than
500 patients in this two-year study
 Rosuvastatin 40 mg was well tolerated with a safety profile
consistent with the existing extensive safety database
 Increases in ALT* were low (0.2%)
 There were no clinically significant increases in CK**
observed in the core laboratory and there were no cases of
rhabdomyolysis
 The number of clinical events in the study was too small for
any meaningful analysis of the relationship between
progression rate and morbidity or mortality
*Alanine aminotransferase (ALT) >3xULN on two consecutive visits
**Creatine
kinase (CK) >10 ULN
Adapted from Nissen et al. JAMA 2006;295(13):1556-65.
ASTEROID Overall Summary
 ASTEROID showed that in statin-naïve patients with CAD,
regression of coronary atherosclerosis can be achieved with
intensive statin therapy with rosuvastatin 40 mg:
– Reducing all three IVUS measures of coronary atheroma
volume
– Reducing %DS and increasing MLD as measured by QCA
 Rosuvastatin 40 mg significantly reduced LDL-C by 53% to
61 mg/dL (1.58 mmol/L) and significantly raised HDL-C by
14.7% to 49 mg/dL (1.27 mmol/L)
 Rosuvastatin 40 mg was well tolerated with a safety profile
consistent with the existing extensive safety database
Adapted from Nissen et al. JAMA 2006;295(13):1556-65, Ballantyne et al. Circulation 2008;in press.
Clinical Perspective
 Atherosclerosis is the underlying cause of heart disease, the
world’s number one killer
 Rosuvastatin is the only statin to show regression of coronary
atherosclerosis in a major clinical study
 In ASTEROID, two imaging modalities that measure different
parameters and focus on different segments of the coronary
arteries have demonstrated concordant improvements in both
IVUS measurements of atheroma volume and angiographic
measurements of lumen dimension consistent with regression
of atherosclerosis with intensive rosuvastatin therapy
 Rosuvastatin, which provides significant reductions in LDL-C
and increases in HDL-C, has demonstrated a significant
impact on atherosclerosis across the spectrum of the disease;
with METEOR, in subjects with early disease and low coronary
heart disease (CHD) risk; and with ASTEROID in patients with
established disease and a high risk of CHD events