Slides - Clinical Trial Results

Report
Effect of high-intensity statin therapy on atherosclerosis
in non-infarct related coronary arteries:
a serial intravascular ultrasonography study
IBIS-4 (Integrated Biomarkers and Imaging Study)
Lorenz Räber, Masanori Taniwaki, Serge Zaugg
Henning Kelbaek, Marco Roffi, Lene Holmvang
Stephane Noble, Giovanni Pedrazzini, Aris Moschovitis
Thomas F. Lüscher, Christian M. Matter, Patrick W. Serruys
Peter Jüni, Hector M. Garcia Garcia, Stephan Windecker
Bern University Hospital, Switzerland
Speaker’s name: Lorenz Räber, MD
 I have the following potential conflicts of interest to report:
 Research contracts
 Consulting
 Employment in industry
 Stockholder of a healthcare company
 Owner of a healthcare company
 Other(s):
 I do not have any potential conflict of interest
X
The IBIS-4 trial was supported by the Swiss National Science Foundation
and an unrestricted grant by Volcano Europe, Belgium and
Biosensors S.A., Switzerland.
BACKGROUND I
• Statins potently reduce cardiovascular adverse events and are
particularly effective in patients with acute coronary syndromes.
• Intravascular ultrasound studies have shown that high
intensity statin therapy results in atheroma regression in patients
with stable, non-obstructive CAD.
• STEMI patients are at high risk for recurrent atherothrombotic events
related to multi-focal disease with a high prevalence of vulnerable
plaques extending beyond the culprit lesion site and
an inflammatory milieu, which triggers plaque growth.
HYPOTHESIS I
Coronary atherosclerosis regression can be achieved
by high-intensity rosuvastatin therapy (40 mg daily)
in the proximal segments of non-infarct related arteries
(non-IRA) of STEMI patients within 13 months.
BACKGROUND II
• Plaque phenotype is relevant in the pathogenesis of future
cardiovascular events. Therefore, it is of interest to study
changes in plaque composition in response to high-intensity
statin therapy.
• Radiofrequency-IVUS has been validated for the characterization
of plaque composition including necrotic core based on ex-vivo
histological analyses.
HYPOTHESIS II
High-intensity rosuvastatin therapy results in
a reduction of RF-IVUS defined necrotic core
and a decrease in the frequency of RF-IVUS defined
thin cap fibroatheromas (TCFA).
STUDY DESIGN
1161 Acute STEMI Patients
1:1 Randomization
Biomatrix vs. BMS
(COMFORTABLE AMI)
11 international sites
Inclusion 9/2009 - 1/2011
TIMI >2
Hemodynamic stability
Age <90 yrs
No stenosis >50% in non-IRA
Anatomically suitable
5 Sites (N=103)
1° Endpoint @ 1 Year
Räber et al. JAMA 2012
2 year follow-up
Bern (60)
Copenhagen (21)
Geneva (13)
Lugano (6)
Zurich (3)
103 Acute STEMI
Patients
Rosuvastatin
20 mg
over 2 Weeks
Rosuvastatin
40mg
over 13 Mo
1° Endpoint @ 13mo
5 year follow-up
IVUS
RF-IVUS
OCT
Change in % Atheroma Volume
Change in % Necrotic Core
IVUS
RF-IVUS
OCT
IRA (not reported)
STUDY DESIGN
Baseline
Proximal part (>40 mm)
2 major non-IRA vessels
1 IRA vessel (stent)
Matched BL - FUP
13 Months F/U
Non-IRA
METHODS AND DEFINITIONS
IVUS console
Volcano Cooperation, Belgium
IVUS catheter
20 MHz, Eagle Eye
Progression /
Regression analysis
Core Laboratory
(Cardialysis B.V., Rotterdam, NL)
Lesion type analysis
Bern University Hospital (LR, MT, HGG)
Analysis software
QIVUS, Medis, Leiden, NL
Analysis interval
0.4 mm
Analysts
Blinded for temporal sequence
Statistical analysis
Clinical Trials Unit, University of Bern
RF-IVUS LESION CLASSIFICATION
Lesion = > 40% plaque burden in > 3 consecutive frames
Confluent necrotic core > 10%
NO
YES
>15% Fibrofatty
30° NC abutting lumen in 3 cons.
frames
NO
YES
NO
YES
Path. Int. Thick.
Fibrous
ThCFA
TCFA
>10% confluent calcium
Fibrocacific
IBIS-4 TRIAL: FLOW OF PATIENTS
103 patients
206 major coronary vessels
34 vessels with
unsuccessful imaging
Successful imaging @ baseline
101 patients
172 vessels (IVUS and RV-IVUS)
Successful serial imaging @ 13 months
82 patients (80%)
146 vessels (IVUS and RF-IVUS)
12 patients refused
FUP (12%)
11 vessels with
unsuccessful imaging
CLINICAL CHARACTERISTICS
Serial Imaging
(N=82)
Age
No Serial Imaging
(N=21)
P value
58.5 ± 9.9
57.1 ± 12.9
0.58
7.3%
19.0%
0.12
27.5 ± 3.8
29.0 ± 5.5
0.17
Diabetes
11.0%
19.0%
0.46
Hypertension
47.6%
42.9%
0.81
Hyperlipidemia
43.9%
9.8%
28.6%
14.3%
0.23
0.69
Time from symptom onset to
balloon inflation (h)
4.4 (2.8; 8.0)
4.0 (2.8; 6.5)
0.67
Left ventricular function
47.5 ± 8.8%
49.4 ± 12.0%
0.47
Female gender
BMI
Prior statin use
MEDICATION @ FOLLOW-UP
30 days
N=82
Statin
12 months
N=82
100%
99%
10 mg
1%
2%
20 mg
11%
20%
40 mg
84%
72%
40 mg
1%
1%
80 mg
2%
2%
Any DAPT
100%
95%
Betablocker
95%
84%
ACE inhibitor
73%
56%
Rosuvastatin
Atorvastatin
LIPID LEVELS @ 30 DAYS AND 13 MONTHS
-42%
p<0.0001
+8%
p<0.0001
1.2 mmol/L
3.3 mmol/L
1.1 mmol/L
1.9 mmol/L
STUDY SEGMENTS: NON-INFARCT RELATED ARTERIES
VESSEL TYPE AND LENGTH
LAD 26%
Infarct Vessel
LAD 43%
RCA 39%
LCX 18%
RCA 35 %
LCX 39 %
Vessel length per patient @ BL 64.4 ± 27.2 mm
Vessel length per patient @ FUP 64.5 ± 26.9 mm
PRIMARY (AND SECONDARY) IVUS ENDPOINT MEASURES
1° EP Change in Percent Atheroma Volume
0
43.95 ± 9.66 %
-0.2
-0.9% (-1.56 to -0.25)
P=0.007
-0.4
-0.6
43.02 ± 9.82 %
-0.8
-1
Average Atheroma
Area (mm2)
Normalized
TAV (mm3)
7.1 ± 3.22
6.75 ± 3.15
-0.35 (-0.48 to -0.21)
<0.001
248.4 ± 112.69
235.95 ± 110.25
-12.18 (-16.91 to -7.44)
<0.001
Baseline
Regression
%
80
67.5%
Plaque burden
57.8%
13 months
PROPORTION OF PATIENTS
WITH PLAQUE REGRESSION
In one
non-IRA
70
In both
non-IRA
60
54%
50
40
30
20
10
0
74%
STRATIFIED ANALYSIS ACCORDING TO LIPID LEVELS
Change in PAV
PRIMARY RF-IVUS ENDPOINT
Change Percent Necrotic Core
Baseline
13 Months F/U
21.14 ± 7.43 %
21.02 ± 7.04 %
Δ -0.05 % (-1.05 to 0.96), p=0.93
Exploratory EP: Absolute Change Necrotic Core
0.92 ± 0.73 mm²
0.84 ± 0.68 mm²
Δ -0.08 mm² (-0.13 to –0.03), p=0.002
RF-IVUS LESION PHENOTYPE ANALYSIS
82 serially assessed patients with 146 analysed vessels
13 months follow-up
Baseline
75%
TCFA
13%
ThCFA
6%
PIT
0
20
15%
ThCFA
165 lesions
5%
Other
70%
TCFA
40
60
Other: fibrocalcific, fibrotic
1 lesion was not present at BL but at FUP
80
158 lesions
PIT
5%
Other
6%
4%
Resolved
0
20
40
60
80
LIMITATIONS
• No formal sample size calculation as this was a pre-specified
substudy of a RCT comparing DES with BMS in STEMI patients.
- Exploratory analysis using confidence intervals shows 80% power
to detect a PAV reduction of 0.94%.
• Serial imaging study without control group.
- Absence of high-intensity statin therapy was considered clinically
unacceptable.
• Only selected STEMI patients underwent serial imaging.
- Multi-vessel imaging in the setting of STEMI is technically
demanding and can only be performed in stabilized STEMI
patients.
• Imaging was obtained at 13 months, which might affect the ability
to detect long-term changes in plaque composition and phenotype.
CONCLUSIONS
• The proximal segments of non-IRA of STEMI patients feature a high
atherosclerotic plaque burden with the majority of lesions
characterized as thin-cap fibroatheromas.
• High-intensity statin therapy throughout 13 months is associated
with a significant reduction of coronary atherosclerosis.
• High-intensity statin therapy did not change the proportion of
necrotic core and plaque phenotypes.

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