Impact of ezetimibe on stabilization & regression of - - PowerPoint PPT Presentation

Impact of ezetimibe on stabilization & regression of intracoronary plaque as assessed by angioscopy

Yasunori Ueda, MD, PhD, FACC, FESC Director, Cardiovascular Division, Osaka National Hospital President, Japanese Association of Cardioangioscopy

Osaka National Hospital

Osaka National Hospital

The Japanese Circulation Society

COI Disclosure

Yasunori Ueda :

Remuneration for lecture: Sanofi. Scholarship fund: Abbot Vascular and Bayer.

Osaka National Hospital

Process of atherosclerosis & acute MI onset From angioscopic viewpoint

Angioscopy can visualize full-color real-time 4D image

Osaka National Hospital 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 LAD:1-6 LCx:7-10 RCA:11-14 LAD:1-6 LCx:7-10 RCA:11-14 64y.o. female 64y.o. female

Normal Coronary Artery = No yellow plaque

Osaka Police Hospital

Osaka National Hospital

Unstable Angina = Yellow plaque & thrombus

Osaka Police Hospital

Osaka National Hospital

1 9

1 2 3 4 5 6 7 8 9

Acute Myocardial Infarction = Yellow plaque & thrombus

Ueda et al. J Invasive Cardiol. 2006

Osaka National Hospital

Acute MI Unstable angina

Osaka Police Hospital

Culprit of Acute Coronary Syndrome

Osaka National Hospital

Vulnerable plaque

Grade 0 Grade 1 Grade 2 Grade 3

* p<0.05 vs. Grade 1 † p<0.05 vs. Grade 2

. 20 . 40 . 60 . 80 100 1 2 3 Yellow color grade * † n=73 (%)

* p<0.05 vs. Grade 1 † p<0.05 vs. Grade 2 Non-Stenotic Yellow Plaques

1 2 3 100 80 60 40 20 (%) * † n=345 n=721 n=187 Yellow color grade n=26 n=104 n=61

PCI Target Lesions

Incidence of plaque disruption

Ueda et al. Am Heart J 2004

Disruption = having thrombus = rupture or erosion

Osaka National Hospital

Yellow+ Yellow –

Ueda et al. J Interven Cardiol, 2007 Ueda et al. J Am Coll Cardiol. 2001

Acute MI in young patients (<40 yrs)

<40yrs 40–50yrs ≥50yrs Yellow+ 44% 91% 94% Smoking 88% 62% 48%

N=893

Thrombogenic white lesion = Plaque erosion

Osaka National Hospital

White Yellow

Acute MI Unstable AP Stable AP 92.7% 94.7% 47.2%

Majority of ACS is caused by yellow plaque

Pathologically, 30%: erosion and 70%: rupture Angioscopically, both rupture and erosion

• ccur at yellow plaque

Osaka Police Hospital

Osaka National Hospital

Sanidas et al. Am J Cardiol. 2011

Ruptured plaque & Non-ruptured (erosion) plaque = Yellow plaque

Ruptured plaque Non-Ruptured plaque Similar VH findings between ruptured and non-ruptured plaques

Osaka National Hospital

Plaque formation Plaque disruption Myocardial infarction

Progression of Atherosclerosis and Acute MI Onset

Osaka Police Hospital

Osaka National Hospital 1 1 2 2 3 3 4 4 5 5 6 6 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 7 7 8 8 9 9 10 10 11 11 12 12 11 11 12 12 Culprit lesion Culprit lesion

Asakura and Ueda et al. J Am Coll Cardiol. 2001

Vulnerable patient = Multiple yellow plaques

Osaka National Hospital

Ohtani and Ueda et al. J Am Coll Cardiol. 2006

Number of Yellow Plaque and Future ACS

Incidence of ACS events Follow-up period (%) 14 NYP =0,1 NYP ≥ 2 p=0.02 12 10 8 6 4 2 7 6 5 4 3 2 1 (yrs)

Osaka National Hospital

Ohtani and Ueda et al. J Am Coll Cardiol. 2006

5 10 15 (%) 20 NYP=0/1 NYP>2 2.2-fold P=0.02 Incidence of ACS events NYP>5 4.1% 9.0% 15.6% 3.8-fold

Number of Yellow Plaque and Future ACS

Osaka National Hospital

Yellow Plaques N=651 (in 165 pts) Disrupted Plaques N=168 (26%) ACS Culprit N=56 (33%) Non-ACS Culprit N=31 (19%) Non-Culprit N=81 (48%) Non-disrupted Plaques N=483 (74%)

Masumura and Ueda et al. Circ J. 2010

Approximately 4 yellow plaques, 1 grade-3 yellow plaque and 1 disrupted yellow plaque were detected per vessel.

Silent Plaque Disruption w/o ACS Onset

Osaka National Hospital

2 weeks later Unstable angina

Ueda et al. Herz 2003

From Plaque Rupture to Acute MI Onset

Osaka National Hospital

Osaka Police Hospital

Silent Plaque Rupture w/o ACS Onset

Osaka National Hospital

Ueda et al. J Invasive Cardiol. 2006

Myocardial infarction Plaque disruption Healed rupture Unstable angina

From Plaque Rupture to Acute MI Onset

Osaka National Hospital

Plaque rupture Thrombosis +Spasm ACS Healed ACS

From Plaque Formation to ACS Onset

Osaka National Hospital

Burke A P et al. Circulation 2001

Repeated Rupture Forms Large Plaque Burden

Osaka National Hospital

Rittersma S Z et al. Circulation. 2005;111:1160-1165

211 STEMI <6hrs after onset

<1 day 1-5 days >5 days

Time From Plaque Rupture to ACS Onset

Osaka National Hospital 211 STEMI <6hrs after onset <1 day 1-5 days >5 days <1 day 1-5 days >5 days

Rittersma S Z et al. Circulation. 2005;111:1160-1165

Time From Plaque Rupture to ACS Onset

Osaka National Hospital

Time From Plaque Rupture to ACS Onset

Acute MI Unstable angina Silent plaque rupture

Healed Healed Thrombus formation

½: <24hrs ½: Days to weeks

Osaka National Hospital

ACS Healed

Determinants of ACS Onset after Plaque Rupture

Plaque burden Lumen area Size and morphology of rupture Blood thrombogenicity

Osaka National Hospital

Stone GW et al. N Engl J Med 2011

Event Rates for Lesions at a Median FU of 3.4 Years

A Prospective Natural-History Study of Coronary Atherosclerosis (PROSPECT study)

PROSPECT study

Osaka National Hospital

Matsuo and Ueda et al. Thromb Res. 2011

Acute Myocardial Infarction Control

Highly Thrombogenic Blood in Acute MI

Measured by MC-FAN

Osaka National Hospital 1000 2000 3000 4000 5000 6000 7000 8000 9000 Acute Chronic Control

BVI

p<0.001 vs. Acute

ǂp<0.001 vs. Control

ǂ

Myocardial Infarction Matsuo and Ueda et al. Thromb Res. 2011

Highly Thrombogenic Blood in Acute MI

Measured by MC-FAN

Blood thrombogenicity increases transiently in the acute phase of MI Transient increase of blood thrombogenicity may be the cause of MI onset

Osaka National Hospital

Plaque formation Plaque disruption Occlusive thrombus formation

No yellow plaque By lipid-lowering ? No plaque with thrombus By anti-inflammation ? No ACS event By anti-platelet/ anti-coagulation ?

How to Prevent ACS Onset and How to Assess It

ACS Onset

Osaka National Hospital

BMS, Immediate

Ueda et al. J Am Coll Cardiol. 1994

STENT STENT

3 3 1 1 2 2 4 4 3 3 1 1 4 4

Disrupted yellow plaque

Neointima in BMS～Sealing effect

Osaka National Hospital STENT STENT

1 1 3 3 1 1 2 2 3 3 4 4 4 4

Stent was covered by neointima Yellow plaque was also covered by neointima

BMS, 3 months

Ueda et al. J Am Coll Cardiol. 1994

Neointima in BMS～Sealing effect

Osaka National Hospital BMS, 3 years BMS, 8 years No yellow plaque No event Disrupted yellow plaque Unstable angina

= Yellow plaque is the cause of event

Osaka Police Hospital

Neoatherosclerosis in BMS

Osaka National Hospital

Single center, prospective, follow-up study to examine if angioscopic findings (yellow color, poor neointima coverage, and thrombus) at 1 year after implantation of DES can predict the event of very late stent failure (death or MI/ UA/ revascularization at the target stent). Enrollment started in 2004.

PCI with DES 1Y FU with Angioscopy (Enrollment) Follow up for events of very late stent failure (death, MI, UA or TLR)

DESNOTE study

Detect the Event of very late Stent failure from the drug- eluting stent NOT well covered by nEointima determined by angioscopy

Ueda et al. JACC Interv. 2015

Osaka National Hospital

DESNOTE study

1st Endpoint

Ueda et al. JACC Interv. 2015

vs.

Osaka National Hospital

DESNOTE study

Ueda et al. JACC Interv. 2015

Hazard ratio [95% CI] P value Presence of yellow plaque 8.55 [1.13–66.7] 0.03 Low-density lipoprotein cholesterol change from baseline to the end

• f follow-up

(mg/dL) 1.03 [1.01–1.04] 0.001 Low-density lipoprotein cholesterol at the end of follow-up (mg/dL) 0.98 [0.97–1.00] 0.07 Stent diameter (mm) 0.28 [0.08–1.00] 0.05

Stent type (1st vs. 2nd generation), age, gender, hypertension, diabetes mellitus, current smoking, stenting for acute coronary syndrome, serum low-density lipoprotein cholesterol, serum high-density lipoprotein cholesterol, serum triglyceride, serum low-density lipoprotein cholesterol change from baseline to follow-up, serum high-density lipoprotein cholesterol change from baseline to follow-up, serum triglyceride change from baseline to follow-up, aspirin use, ticlopidin/clopidogrel use, statin use, stent diameter, total stent length, presence of yellow plaque, presence of thrombus, and minimum neointima coverage grade were included as variables.

Multivariable Cox regression analysis to evaluate the risk factors of VLSF including the data at the end of follow-up

Osaka National Hospital

Komatsu et al. Circ J 2015; 79 :742-750

Atherosclerosis in Aorta

Osaka National Hospital 2 3 4 5 6 7

３ ２ ４ ５ ６ ７

By courtesy of Dr. K. Kodama.

Atherosclerosis in Aorta

Osaka National Hospital

Mizote and Ueda et al. Circulation. 2005

Plaque debris embolization Ruptured plaque

Atheromatous embolization

Osaka National Hospital

Atheromatous embolization

Cholesterol crystal emboli

YP Liew and JR Bartholomew. Vascular Medicine 2005; 10:309-326

Osaka National Hospital

Caused by atheromatous embolization/ cholesterol crystal embolization from Aorta?

Cerebral infarction Dementia Chronic kidney disease Lower limb ischemia

Osaka National Hospital

Assessment of lipid-lowering therapy by angioscopy

Osaka National Hospital

① ② ③ ④ ① ② ③ ④ ① ② ③ ④ ① ② ③ ④

Before After 80 weeks Atorvastatin (10mg/day)

Okada and Ueda et al. J Interven Cardiol, 2007

Plaque Stabilization = reduction of yellow color

Osaka National Hospital

Hirayama A et al. Circ J, 2009

TWINS STUDY

Plaque Stabilization and Regression

Okada et al. Circ J, 2012

Osaka National Hospital

Hirayama A et al. Circ J, 2009

TWINS STUDY

Plaque Stabilization and Regression

Osaka National Hospital 2.0 1.5 1.0

P<0.001**

Mean grade of yellow plaque

• 25
• 20
• 15
• 10
• 5

Change in plaque volume (%) baseline 28 weeks 80 weeks

P=0.003*** P<0.001** P=0.024* P=0.012* P=0.508*

Hirayama A et al. Circ J, 2009

TWINS STUDY

20 patients of matched data 58 yellow plaques 30 IVUS segments

Plaque Stabilization and Regression

Osaka National Hospital

Okada et al. Circ J, 2012

TWINS STUDY

Plaque Stabilization and Regression

Osaka National Hospital

LDL-C and Lip ipid Changes

1 Yr Mean LDL-C TC TG HDL hsCRP Simva 69.9 145.1 137.1 48.1 3.8 EZ/Simva 53.2 125.8 120.4 48.7 3.3 Δ in mg/dL

• 16.7
• 19.3
• 16.7

+0.6

• 0.5

Median Time avg 69.5 vs. 53.7 mg/dL Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Osaka National Hospital

In Indiv ivid idual Cardio iovascular Endpoints and CVD/MI/Stroke

HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc ≥ 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003

Ezetimibe/Simva Better Simva Better 0.6 1.0 1.4

*7-year event rates (%) Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12

Osaka National Hospital

ZIPANGU study

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Study Design

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Change in LDL-C

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Change in Yellow Color Grade

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Influence of Baseline Grade

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Change in %Plaque Volume

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Comparison with Other Studies

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Influence of LDL-C

Ueda Y et al. Circ J 2017

Osaka National Hospital

ZIPANGU study: Influence of Absorption/ Synthesis

Ueda Y et al. Circ J 2017

Absorption (sitosterol and campesterol) Synthesis (lathosterol)

Osaka National Hospital

PRECISE-IVUS study: Change in LDL-C

Tsujita K et al. JACC 2015

Osaka National Hospital

PRECISE-IVUS study: Change in %Plaque Volume

Tsujita K et al. JACC 2015

Osaka National Hospital

PRECISE-IVUS study: Influence of LDL-C

Tsujita K et al. JACC 2015

Osaka National Hospital 1 1 2 2 3 3 4 4 5 5 6 6 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 7 7 8 8 9 9 10 10 11 11 12 12 11 11 12 12 Culprit lesion Culprit lesion 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 9 9 10 10 11 11 12 12 13 13 14 14 LAD:1-6 LCx:7-10 RCA:11-14 LAD:1-6 LCx:7-10 RCA:11-14 64y.o. female 64y.o. female

Stabilization in average Destabilization of some plaques

All plaques should be stabilized

Osaka National Hospital

Conclusion

• ACS always occurs at yellow plaque and number of yellow plaques shows

future ACS risk.

• When blood thrombogenicity increases, ACS may occur at a disrupted plaque.
• Angioscopy can evaluate plaque stabilization as the reduction of yellow color.
• Plaque stabilization (color reduction) was similarly achieved by statin

monotherapy and by combination therapy with ezetimibe.

• Plaque regression (volume reduction) was achieved by combination therapy,

but not by statin monotherapy.

• Our results on plaque volume reduction was consistent with other studies.
• Stabilization of plaques in Aorta may be a next target of cholesterol lowering

therapy.

Osaka National Hospital

Thank you.