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 typically extending beyond the culprit lesion site.

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 > 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

Δ -1.4 mmol/Lp<0.0001

1.1 mmol/L

1.2 mmol/L

Δ -0.1 mmol/Lp<0.0001

RCA 35 % RCX 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

PRIMARY (AND SECONDARY) IVUS ENDPOINT MEASURES

43.95 ± 9.66 mm2

43.02 ± 9.82 mm2

-1-0.9-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.1

0

1° EP 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 BMS with DES 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 athero- sclerotic plaque burden with the majority of lesions characterized as RV-IVUS defined 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 RF-IVUS defined necrotic core and plaque phenotypes.