Appendix
Effect of high-intensity statin therapy on atherosclerosis in non-infarct related coronary
arteries (IBIS-4): a serial intravascular ultrasonography study
Räber L. et al.
for the IBIS 4 Investigators (NCT00962416)
IBIS-4= Integrated Biomarkers and Imaging Study-4
Calculation of IVUS endpoints
Plaque area was calculated as external elastic membrane area - lumen area. Plaque burden
was defined for each frame as 100*(Plaque area /external elastic membrane area). The
most diseased 10 mm segment at baseline was defined as a 10 mm region of consecutive
frames with the highest average plaque burden. Total atheroma volume and external elastic
membrane volume were obtained by linear interpolation of plaque area and external elastic
membrane area respectively with inter frame distance (i.e. trapezoidal rule or Simpson’s
rule). Average atheroma area mm3/mm was calculated as total atheroma volume/ROI
length. Normalized total atheroma volume was calculated as average atheroma
area*median(ROI length), where the median was taken over baseline and follow-up vessels.
Percent atheroma volume, the primary IVUS endpoint, was calculated as
Percent atheroma volume = 100
Total atheroma volume
External elastic membrane volume
Average Area of Necrotic Core tissue, the RF IVUS endpoint, was derived as
Average area of necrotic core tissue =
∑ Necrotic core area
N
where N is the number of frames. The RF area was the part of the plaque area that was
partitioned into four RF IVUS tissue types by the RF algorithm and excluded the area
classified as media. The secondary endpoint of this study was RF IVUS derived percent
volume necrotic core tissue, which was calculated as follows
Percent volume necrotic core tissue = 100
∑ Necrotic core area
∑ Radiofrequency area
Radiofrequency ultrasonography defined lesion analysis
A lesion consisted of all consecutive frames with plaque burden >40% within the ROI.
Lesions were considered separate when the distance between them was more than 5 mm.
Lesions were categorized in a blind fashion (blinded for time point of imaging) during a
consensus session by two independent readers into: (i) pathological intimal thickening; (ii)
fibrotic; (iii) fibrocalcific; (iv) thick cap fibroatheroma; (v) thin cap fibroatheroma (TCFA). In
case of disagreement, a third reader was consulted to reach agreement. The validation of
the RF-IVUS lesion characterization against pathology has been evaluated in the CAPITAL
study. The diagnostic accuracy for the detection of TCFA was above 95%. Importantly, the
lesion phenotypes were assessed in a paired fashion, that is matched frames were
simultaneously evaluated to ensure a proper anatomical comparison. This was achieved by
using an IVUS matcher software that allows for the synchronization of the two IVUS
pullbacks at many different anatomical landmarks within the ROI.
Table A1. Baseline Clinical Characteristics of all STEMI patients enrolled at the 5
intracoronary imaging sites
Number of patients
Age
Female sex
BMI
Cardiovascular risk factors
Diabetes
Hypertension
Hypercholesterolemia*
Current smoker
Family history of CAD
Renal failure**
Previous myocardial infarction
Previous PCls
Clinical presentation
Time from symptom onset to balloon
inflation (min)
Left ventricular ejection fraction
(angiography)
Not enrolled
into imaging
substudy
N = 499§
61.8 ± 12.3
104 (20.8%)
26.8 ± 4.0
70 (14.0%)
221 (44.3%)
265 (53.4%)
247 (50.1%)
133 (27.1%)
34 (6.9%)
26 (5.2%)
28 (5.6%)
244 (164; 435)
48.2 ± 10.5
Enrolled into
imaging
substudy
N = 103
58.2 ± 10.5
10 (9.7%)
27.8 ± 4.2
13
48
42
47
31
5
P value
0.01
0.01
0.02
(12.6%)
(46.6%)
(40.8%)
(45.6%)
(31.0%)
(5.0%)
0.88
0.67
0.02
0.45
0.46
0.66
2 (1.9%)
1 (1.0%)
0.20
0.04
258 (170; 472)
47.8 ± 9.4
0.80
0.76
Resuscitation prior to hospital arrival
8 (1.6%)
5 (4.9%)
0.05
Values reported as No. (%); mean ± sd; or median (interquartile range)
§ Only patients from imaging centers included: Bern, Copenhagen, Geneva, Lugano,
Zuerich
* Total cholesterol >5.0 mmol or 190mg/dl or requiring treatment
**<60 eGFR
Table A2. Serial Intravascular Ultrasonography Results: Sensitivity Analysis Using One Vessel per Patient
Baseline
Mean ± SD
82 Patients
82 Vessels
Follow-up
Mean ± SD
82 Patients
82 Vessels
Absolute change
Mean change (95% CI)
P value
Entire regions
Region Length (mm)
38.24 ± 16.62
37.31 ± 16.95
-0.93 (-2.44 to 0.58)
0.225
2
Average Lumen Area (mm )
8.13 ± 3.01
7.96 ± 2.68
-0.16 (-0.33 to 0)
0.054
Average Vessel Area (mm2)
15.02 ± 5.61
14.47 ± 5.21
-0.55 (-0.78 to -0.32)
<0.001
Primary efficacy parameter
Percent Atheroma Volume (%)
44.62 ± 9.39
43.55 ± 9.46
-1.07 (-1.86 to -0.28)
0.009
Secondary efficacy parameters
Total Atheroma Volume (mm3)
263.93 ± 157.88
245.06 ± 156.31
-18.87 (-32.11 to -5.63)
0.006
2
Average Atheroma Area (mm )
6.88 ± 3.18
6.5 ± 3.11
-0.38 (-0.55 to -0.2)
<0.001
3
Normalized TAV (mm )
240.7 ± 111.07
227.53 ± 108.74
-13.17 (-19.23 to -7.1)
<0.001
Most diseased 10mm segments
Region Length (mm)
9.97 ± 0.14
9.93 ± 1.91
-0.04 (-0.46 to 0.39)
0.868
Average Lumen Area (mm2)
7.16 ± 2.82
7.37 ± 2.87
0.21 (-0.07 to 0.49)
0.141
2
Average Vessel Area (mm )
15.91 ± 5.85
15.22 ± 5.7
-0.68 (-1.06 to -0.31)
0.001
Primary efficacy parameter
Percent Atheroma Volume (%)
53.58 ± 12.22
50.33 ± 11.64
-3.25 (-4.51 to -2)
<0.001
Secondary efficacy parameters
Total Atheroma Volume (mm3)
87.34 ± 40.38
78.62 ± 41.62
-8.71 (-13.2 to -4.22)
<0.001
2
Average Atheroma Area (mm )
8.76 ± 4.04
7.86 ± 3.69
-0.9 (-1.19 to -0.6)
<0.001
3
Normalized TAV (mm )
87.22 ± 40.25
78.3 ± 36.79
-8.92 (-11.89 to -5.95)
<0.001
Additional sensitivity analysis. Only uses data from one vessel per patient in case there were two, giving precedence to LAD over LCX over
RCA. For descriptive purposes the crude mean over all vessels is reported for baseline and follow-up. Two-sided p-values to test if change is
different from zero and 95% CIs are from linear models. TAV: Total Atheroma Volume
Table A3. Serial Radiofrequency Ultrasonography Analysis
Baseline
Follow-up
Absolute change
Mean change (95%
CI)
Nb. pat. (vessels): 82 (146)
Mean ± SD
Mean ± SD
p-value
Entire regions
Average Area NC (mm2)
0.92 ± 0.73
0.84 ± 0.68
-0.08 (-0.13 to -0.03)
0.002
2
Average Area DC (mm )
0.39 ± 0.4
0.4 ± 0.42
0.02 (-0.01 to 0.04)
0.243
Average Area FI (mm2)
2.28 ± 1.45
2.05 ± 1.39
-0.24 (-0.32 to -0.15)
0.000
2
Average Area FF (mm )
0.42 ± 0.37
0.4 ± 0.39
-0.02 (-0.07 to 0.03)
0.505
Most diseased 10mm segments
Average Area NC (mm2)
1.4 ± 1.06
1.19 ± 0.93
-0.21 (-0.31 to -0.1)
0.000
Average Area DC (mm2)
0.56 ± 0.59
0.56 ± 0.57
0 (-0.05 to 0.05)
0.970
2
Average Area FI (mm )
3.03 ± 1.8
2.56 ± 1.6
-0.48 (-0.61 to -0.35)
0.000
2
Average Area FF (mm )
0.58 ± 0.54
0.5 ± 0.49
-0.08 (-0.14 to -0.01)
0.018
For descriptive purposes the crude mean over all vessels is reported for baseline and follow-up. Two-sided p-values to test if change is different from zero are
from linear mixed models (patient as random intercept). NC: necrotic core tissue, DC: dense calcium tissue, FI: fibrous tissue, FF: fibrofatty tissue.