Regression and Progression of Atherosclerosis:
Insights from Intravascular Ultrasound
Steven E. Nissen MD
Disclosure
Consulting: Many companies
Clinical Trials:AstraZeneca, Eli Lilly, Takeda, Novartis, Resverlogix, DaiichiSankyo, Sanofi-Aventis, Roche, and Pfizer.
Companies are directed to pay any honoraria directly to charity. No personal
reimbursement is accepted for directing or participating in clinical trials.
Heart attacks: gone with the century?
Brown MS, Goldstein JL.
Science. 1996 May 3;272(5262):629.
Beyond Statins: Is LDL Reduction Enough?
700
600
500
CV Death/MI
(Number
of events)
34%
reduction
Placebo
Treated
400
300
31%
reduction
200
100
0
4S Trial
WOSCOPS Trial
2° prevention trial
with simvastatin
1° prevention trial
with pravastatin
Deep Fried Mars Bar
‘The World’s Most Atherogenic Food’
Single Vessel Left Anterior Descending Disease
Intravascular Ultrasound Coronary Imaging
Rotating Transducer
Coronary Atheroma
Glagov Remodeling Phenomenon
Early Atherosclerosis
3.5 mm
Advanced Disease
3.5 mm
Angiographically Normal
Segment of LAD
Low Grade Stenoses Cause Most Infarctions
CAD: The Diagnosis Often Comes Too Late
Transplant Donor: 33 Year Old Male
Left Anterior Descending
Left Circumflex
Transplant Donor: 32 Year Old Female
Left Circumflex
Ramus Branch
Donor Atherosclerosis: 17 Year Old Male
Left Anterior Descending
Magnified View
Tuzcu et al,, in press.
Cholesterol and CAD in a
Low-Cholesterol Population
Relative Risk of
Coronary Heart Disease
9021 Chinese 8-13 Year Follow-up
2
1
0.5
0.25
139 147 155 162 170 178 186
Mean Usual Cholesterol (mg/dL)
Chen et al. BMJ. 1991;303:276-282.
654 patients at 34 centers
Symptomatic CAD, coronary angiography with >20% stenosis
LDL 125 to 210 mg/dL after 8 week washout
Intravascular ultrasound with 30 MHz transducer
Motorized pullback at 0.5 mm/sec through >30 mm
length of single “target” coronary artery
pravastatin 40 mg
18 months
treatment
atorvastatin 80 mg
78 patients withdrew
74 patients withdrew
249 pravastatin patients
253 atorvastatin patients
Follow-up IVUS of originally imaged “target” vessel (n=502)
Ultrasound Measurement of Atheroma Area
Precise Manual Planimetry of EEM and Lumen Borders
EEM Area
Lumen
Area
Atheroma Area
Ultrasound Measurement of Atheroma Volume
Motorized Pullback: Cross-sections Selected at 1 mm Intervals
1 mm spacing
Cross-section 48
Cross-section 26
Cross-section 10
Final Lipid Values and Percent Change
* ANOVA
Primary Endpoint
Percent Change in Atheroma Volume
Progression (p=0.001*)
Percent
Change
In
Atheroma
Volume
p = 0.02†
No change (p=0.98*)
*Wilcoxon signed rank test †ANCOVA of rank transformed results
Pravastatin
Atorvastatin
LDL-C Change vs. Atherosclerosis Progression
Combined atorvastatin
and pravastatin
treatment groups
Nissen et al. N Engl J Med 2005;352:29-38.
mg
0
4
tin
a
t
s
a
Prav
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a
g
“
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g
m
0
8
n
i
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a
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a
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Change in LDL-cholesterol (mg/dL)
Change in Percent Atheroma Volume (%)
LDL-C Change vs. Atherosclerosis Progression
Secondary Endpoint: C
-reactive Protein
C-reactive
Percent reduction in CRP (mean baseline level =2.9 mg/dL)
Percent
Change
(%)
*Wilcoxon rank sum test
p< 0.0001*
Pravastatin
Atorvastatin
Combined atorvastatin
and pravastatin
treatment groups
Change in C-Reactive Protein (mg/L)
Change in Percent Atheroma Volume (%)
CRP Change vs. Atherosclerosis Progression
Correlation Between LDL-C and CRP Change
Atorvastatin 80 mg
r = 0.08
p = 0.17
Pravastatin 40 mg
r = -0.008
p = 0.90
Obsrvational and Pre
-Clinical Studies
Pre-Clinical
• Apolipoprotein A1 Milano is a variant derived from 40 subjects
in the Italian village of Limone sul Garda.
• Apo A1 Milano carriers exhibit mean HDL levels of 17 mg/dL
(0.44 mmol/L) with normal longevity and no atherosclerosis.
A cysteine is substituted for arginine at position 173.
• Recombinant Apo A1 Milano has been complexed with
phospholipid to produce nascent HDL
-like particle. (Esperion)
HDL-like
• Infusions of Apo A1 Milano phospholipid complex in Apo E
deficient mice rapidly (48 hours!!) mobilized lipid and reduced
macrophage content within atherosclerotic lesions.*
*Shah PK et al. Circulation 1998;97:780-785 and Circulation 2001;103:3047-3050.
123 patients at 10 centers screened
Recent myocardial infarction or Acute coronary syndrome
>20% stenosis in a non-intervened vessel
Intravascular ultrasound with 40 MHz transducer
Motorized pullback at 0.5 mm/sec through >30 mm
length of single “target” coronary artery
5 weeks
Placebo 12 pts
1 patients withdrew
Placebo 11 pts
ETC-216 low (23 pts)
2 patients withdrew
ETC-216 low (21 pts)
ETC-216 high (22 pts)
7 patients withdrew
ETC-216 high (15 pts)
Follow-up IVUS of originally imaged “target” vessel (n=47)
ApoA1 Milano: Change in Total Atheroma Volume
-2.9
mm33
P = 0.97
-12.6
mm33
-15.1
mm33
P = 0.007
-14.1
mm33
P< 0.001
P = 0.02
Placebo
Low Dose
High Dose
Combined
EEM area
14.37 mm2
EEM area
11.58 mm2
Lumen area
6.27 mm2
Atheroma
area - 8.10 mm2
Side
Branch
Lumen area
6.23 mm2
Atheroma
area - 5.35 mm2
Side
Branch
1991 patients at 100 centers, North America and Europe
Symptomatic CAD, coronary angiography with >20% stenosis
Diastolic BP ≤ 100 mm Hg
Baseline intravascular ultrasound in 428 participants
placebo
enalapril 20 mg
amlodipine 10 mg
24 months treatment
Intent-to-treat analysis of cardiovascular events (1991 patients)
Repeat intravascular ultrasound examination (274 patients)
Nissen et al. JAMA. 2004;292(18); 2217-2226.
Dr Steven Nissen, Cleveland Clinic Foundation.
Systolic Pressure: All Three Treatment Groups
Nissen et al. JAMA. 2004;292(18); 2217-2226.
Months after randomization
Dr Steven Nissen, Cleveland Clinic Foundation.
CAMELOT: Time to Major Cardiovascular Event
23.1%
20.2%
16.6%
p=0.003
Nissen et al. JAMA. 2004;292(18); 2217-2226.
Dr Steven Nissen, Cleveland Clinic Foundation.
Comparison: Events Rates and IVUS Progression
Patients with baseline systolic blood pressure ≥ mean
24.7%
21.1%
18.3%
Change in Percent Atheroma Volume (%)
2.4
p < 0.001
p = 0.02
2
1.6
1.2
p = 0.20
0.8
0.4
p = 0.76
0
Placebo
Nissen et al. JAMA. 2004;292(18); 2217-2226.
Enalapril Amlodipine
Prior Coronary IVUS Progression Trials
Relationship between LDL-C and Progression Rate
1.8
CAMELOT
placebo
1.2
Median
Change
In Percent
Atheroma
Volume
(%)
0.6
REVERSAL
atorvastatin
0
REVERSAL
pravastatin
ACTIVATE
placebo
A-Plus
placebo
Unexplored
Unexplored
Region
Region
-0.6
-1.2
50
60
70
80
90
Mean LDL-C (mg/dL)
100
110
120
1183 patients screened and 507 patients treated
at 53 centers in US, Canada, Europe and Australia
Intravascular ultrasound with 40 MHz transducer
Motorized pullback at 0.5 mm/sec through >40 mm
length of single “target” coronary artery
rosuvastatin 40 mg for 24 months treatment
158 patients withdrew or did not have
an evaluable final IVUS
Follow-up IVUS of originally imaged “target” vessel (n=349)
Lipid Values and Percent Change (n=349)
* Time-weighted average
† From least square mean
Dual Primary IVUS Efficacy Parameters
Median Change in Percent
Atheroma Volume
Change
In
Percent
Atheroma
Volume
(%)
Median Change in
Most Diseased Subsegment
Change
In
Atheroma
Volume
(mm3)
Regression
p<0.001*
Regression
p<0.001*
*Wilcoxon signed rank test for comparison with baseline
Distribution: Percent Atheroma Volume
80
Regression
63.6%
60
Number
of
Patients
Progression
36.4%
40
20
0
-7
-6
-5
-4
-3
-2
-1
0
1
2
Change in Percent Atheroma Volume (%)
3
4
5
Recent Coronary IVUS Progression Trials
Relationship between LDL-C and Progression Rate
1.8
CAMELOT
placebo
1.2
Median
0.6
Change
In Percent
Atheroma
0
Volume
(%)
REVERSAL
atorvastatin
-0.6
REVERSAL
pravastatin
ACTIVATE
placebo
A-Plus
placebo
r2= 0.95
p<0.001
ASTEROID
rosuvastatin
-1.2
50
60
70
80
90
100
110
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
120
Impact of LDL
-C Lowering on Plaque Progression
LDL-C
2
1
0
-1
-2
40
50
60
70
80
90
100
LDL-C During Treatment, mg/dL
Nicholls S. et al. JAMA. 2007;297:499-508.
110
Impact of HDL
-C Raising on Plaque Progression
HDL-C
2
1
Change
in PAV
(%)
0
-1
-2
10
20
Increase in HDL (%)
Nicholls S. et al. JAMA. 2007;297:499-508.
30
40
Percent Atheroma Volume: LDL
-C and HDL
-C
LDL-C
HDL-C
Median LDL-C - 87.5 mg/dL
Median HDL-C change - 7.5%
1.3%
0.9%
P<
0.0
01
0.2%
-0.2%
LDL-C worse
HDL-C worse
LDL-C worse
HDL-C better
LDL-C better
HDL-C worse
LDL-C better
HDL-C better
Infusion of
ApoA1 Milano
CETP inhibition
with torcetrapib
1188 patients at 137 centers in North America and Europe
Symptomatic CAD, coronary angiography with >20% stenosis
Intravascular ultrasound with 40 MHz transducer
Motorized pullback at 0.5 mm/sec through >40 mm segment
4-10 week run-in atorvastatin 10-80 mg
to achieve LDL-C of 100±15 mg/dL
Atorvastatin
monotherapy
24 months
treatment
Torcetrapib 60mgatorvastatin
140 patients withdrew
135 patients withdrew
446 atorvastatin patients
464 torcetrapib patients
24 Month follow-up IVUS of originally imaged “target” vessel (n=910)
Time Course: Change in LDL-C Levels
Atorvastatin Monotherapy
Difference 19.9%
Torcetrapib-Atorvastatin
Time Course: Change in HDL-C Levels
Torcetrapib-Atorvastatin
Difference 60.8%
Atorvastatin Monotherapy
Cumulative Histogram: Change in Systolic BP
LS Mean difference
4.6 mm Hg
Atorvastatin
Monotherapy
Torcetrapib
Atorvastatin
Primary Efficacy Parameter
Change in Percent Atheroma Volume
p = 0.72†
Change
in percent
atheroma
volume
Atorvastatin
monotherapy
Torcetrapibatorvastatin
Torcetrapib Results: Levels of HDL
-C Achieved
HDL-C
Percent Atheroma Volume
Primary Efficacy Parameter
0.70%
0.30%
0.18%
P<
0.0
01
-0.69%
Quartile 1
<56 mg/dL
Quartile 2
56 to 69 mg/dL
Quartile 3
69 to 86 mg/dL
Quartile 4
>86 mg/dL
Serum Potassium: Effect of Torcetrapib
Atorvastatin
P = 0.08
Torcetrapib-Atorvastatin
P< 0.001
Rimonabant: Weight and Waist Circumference
Waist Circumference (cm)
Change in Body Weight (kg)
-0.5 kg
P< 0.001
-4.3 kg
Change in Waist Circumference (cm)
Body Weight (kg)
Months after Randomization
-1.0 cm
P< 0.001
-4.5 cm
Percent Changes in Biochemical Parameters
HDL-cholesterol
22.4%
P=0.001
in Diabetics (n=248)
HbA1c
1c
0.42%
P<0.001
6.9%
-0.13%
hs C-reactive Protein
P<0.001
-30.9%
Triglycerides
-6.2%
P<0.001
-50.3%
-20.5%
Primary and Secondary IVUS Endpoints
PAV: Primary Endpoint
TAV: Secondary Endpoint
P< 0.001
P = 0.37
0.51
0.88
P=0.22
P=0.03
P =0.09
0.25
-2.2
P=0.03
Placebo
Rimonabant
Recent and Ongoing IVUS Atherosclerosis Trials
Name
Trial Description
Status
Activate
An ACAT inhibitor
NEJM (April ‘06)
Asteroid
Rosuvastatin 40 mg for regression
JAMA (April ’06)
Illustrate
Torcetrapib+statin vs. statin alone
NEJM (March ’07)
Periscope
Pioglitazone vs. glimepiride
JAMA (April ’08)
Stradivarius Rimonabant vs usual care
JAMA (April ’08)
Saturn
Rosuvastatin 40mg vsatorva 80 mg
AHA 2011
Aquarius
aliskerin in normotensive patients
enrolling
Assure
Apo A1 inducer (Resverlogix)
Startup phase