Effect of high-intensity statin therapy on atherosclerosis in non-infarct related coronary arteries:...
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Transcript of Effect of high-intensity statin therapy on atherosclerosis in non-infarct related coronary arteries:...
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 ZauggHenning Kelbaek, Marco Roffi, Lene Holmvang
Stephane Noble, Giovanni Pedrazzini, Aris MoschovitisThomas F. Lüscher, Christian M. Matter, Patrick W. SerruysPeter Jüni, Hector M. Garcia Garcia, Stephan Windecker
Bern University Hospital, Switzerland
The IBIS-4 trial was supported by the Swiss National Science Foundation and an unrestricted grant by Volcano Europe, Belgium andBiosensors S.A., 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 interestX
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 DESIGN1161 Acute STEMI Patients
1:1 Randomization Biomatrix vs. BMS
(COMFORTABLE AMI)11 international sites
Inclusion 9/2009 - 1/2011
1° Endpoint @ 1 YearRäber et al. JAMA 2012
Bern (60)Copenhagen (21)
Geneva (13)Lugano (6)Zurich (3)
103 Acute STEMI Patients
5 Sites (N=103) Rosuvastatin 20 mg
over 2 Weeks
Rosuvastatin 40mg
over 13 Mo
5 year follow-up
2 year follow-up
1° Endpoint @ 13moChange in % Atheroma Volume
Change in % Necrotic Core
IVUSRF-IVUSOCT
IVUSRF-IVUSOCT
TIMI >2Hemodynamic stabilityAge <90 yrsNo stenosis >50% in non-IRAAnatomically suitable
STUDY DESIGN
Baseline
IRA (not reported) Non-IRA
13 Months F/U
Proximal part (>40 mm)2 major non-IRA vessels
1 IRA vessel (stent)Matched BL - FUP
METHODS AND DEFINITIONSIVUS 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
Confluent necrotic core > 10%
NO YES
>15% Fibrofatty
Fibrous ThCFA TCFA
RF-IVUS LESION CLASSIFICATION
30° NC abutting lumen in 3 cons.frames
NO YES
Path. Int. Thick.
>10% confluent calciumFibrocacific
NO YES
Lesion = > 40% plaque burden in > 3 consecutive frames
IBIS-4 TRIAL: FLOW OF PATIENTS103 patients
206 major coronary vessels
Successful imaging @ baseline101 patients
172 vessels (IVUS and RV-IVUS)
Successful serial imaging @ 13 months82 patients (80%)
146 vessels (IVUS and RF-IVUS)
34 vessels with
unsuccessful imaging
12 patients refused FUP (12%)
11 vessels with unsuccessful imaging
CLINICAL CHARACTERISTICS
Serial Imaging(N=82)
No Serial Imaging(N=21)
P value
Age 58.5 ± 9.9 57.1 ± 12.9 0.58Female gender 7.3% 19.0% 0.12BMI 27.5 ± 3.8 29.0 ± 5.5 0.17Diabetes 11.0% 19.0% 0.46Hypertension 47.6% 42.9% 0.81Hyperlipidemia 43.9% 28.6% 0.23Prior statin use 9.8% 14.3% 0.69
Time from symptom onset to balloon inflation (h) 4.4 (2.8; 8.0) 4.0 (2.8; 6.5) 0.67Left ventricular function 47.5 ± 8.8% 49.4 ± 12.0% 0.47
MEDICATION @ FOLLOW-UP30 days
N=8212 months
N=82
Statin 100% 99%
Rosuvastatin
10 mg 1% 2%
20 mg 11% 20%
40 mg 84% 72%
Atorvastatin
40 mg 1% 1%
80 mg 2% 2%
Any DAPT 100% 95%
Betablocker 95% 84%
ACE inhibitor 73% 56%
LIPID LEVELS @ 30 DAYS AND 13 MONTHS
3.3 mmol/L1.9 mmol/L
- 42%p<0.0001
1.1 mmol/L
1.2 mmol/L
+8%p<0.0001
RCA 35 % LCX 39 %
LAD 26%
Vessel length per patient @ BL 64.4 ± 27.2 mmVessel length per patient @ FUP 64.5 ± 26.9 mm
STUDY SEGMENTS: NON-INFARCT RELATED ARTERIESVESSEL TYPE AND LENGTH
Infarct Vessel
LAD 43% RCA 39%LCX 18%
PRIMARY (AND SECONDARY) IVUS ENDPOINT MEASURES
43.95 ± 9.66 %
43.02 ± 9.82 %
-1-0.9-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.1
0
1° EP Change in Percent Atheroma Volume
-0.9% (-1.56 to -0.25)P=0.007
Average Atheroma Area (mm2) 7.1 ± 3.22 6.75 ± 3.15 -0.35 (-0.48 to -0.21) <0.001
Normalized TAV (mm3) 248.4 ± 112.69 235.95 ± 110.25 -12.18 (-16.91 to -7.44) <0.001
PROPORTION OF PATIENTS WITH PLAQUE REGRESSION
0
10
20
30
40
50
60
70
80 74%
54%
In one non-IRA
In bothnon-IRA
RegressionBa
selin
e
Plaque burden
13 m
onth
s
67.5%
57.8%
%
STRATIFIED ANALYSIS ACCORDING TO LIPID LEVELS
Change in PAV
PRIMARY RF-IVUS ENDPOINT
Baseline 13 Months F/U
21.14 ± 7.43 % 21.02 ± 7.04 %
Δ -0.05 % (-1.05 to 0.96), p=0.93
Change Percent Necrotic Core
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
82 serially assessed patients with 146 analysed vessels
Other
PIT
ThCFA
TCFA
0 10 20 30 40 50 60 70 80
Baseline
Resolved
Other
PIT
ThCFA
TCFA
0 10 20 30 40 50 60 70 80
13 months follow-up
165 lesions 158 lesions
RF-IVUS LESION PHENOTYPE ANALYSIS
Other: fibrocalcific, fibrotic1 lesion was not present at BL but at FUP
75%
13%
6%
5%
70%
15%
5%
6%
4%
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.