Fernando Alfonso Departamento de Cardiología

Hospital Universitario de La Princesa

Universidad Autónoma de Madrid

Instituto Investigación Sanitaria (IIS-IP)

Madrid. ESPAÑA

Tratamiento de la

Reestenosis del Stent

Farmacoactivo

XXXI Jornadas SOLACI. 10ª Región CONOSUR

LIIIº Congreso Chileno de Cardiología y Cirugía Cardiovascular

Hotel Patagónico. Puerto Varas. Chile (30 Nov – 1 Dic 2016)

DES Restenosis

Neointimal Proliferation

Predominant Mechanism

Neointimal hyperplasia (SMC)

Curfman GDN. Egl J Med 2007;356(10):1059-60.

Neoatherogenesis

Fibroatheroma. Lipid-laden

Macrophages, calcium (Necrotic Core)

DES 30%, Earlier than BMS

Young, Unstable, Time, DES

Nakazawa G, Virmani R. J Am Coll Cardiol 2011;57:1314–22

Thrombus

DES Fracture

DES Gap

Geographic Miss

Uneven/Undelivered Drug

Non-uniform Strut Distribution

DES Damage

DES Underexpansion (***)

Hypersensitivity

Drug Resistance

Biological Factors

Focal

Diffuse

Mechanical Factors

IVUS / OCT

Treatment of DES ISR:

DES Restenosis

58% Rupture, 52% TCFA, 58% Thrombus

Kang SJ, Mintz GS. Circulation. 2011;123:2954-2963

Rupture

TCFA

TCFA

Thrombus

OCT in 50 Pts with DES ISR

“Layered” DES ISR

VCP DB #1941474 (9M FU RIBS 4)

DES Restenosis

Calcified DES ISR

A +

+

+

+

+

+

B

C

D

E *

*

*

Alfonso F. Calcified In-Stent Restenosis : A Rare Cause of Dilation Failure Requiring Rotational Atherectomy. Circ Cardiovasc Interv 2012;5;e1-e2.

Calcified DES ISR

+ +

+

*

A B

C

Alfonso F. Calcified In-Stent Restenosis : A Rare Cause of Dilation Failure Requiring Rotational Atherectomy. Circ Cardiovasc Interv 2012;5;e1-e2.

“The elusive link between very late ISR and ST”

Ruptured Neoatherosclerosis

B *

PRESTIGE (13/08/2012)

E

*

+

+

+

D

*

+

+

+

A

B C D

E *

T

C

DES Restenosis

Alfonso F, J Am Coll Cardiol 2013;61:155

ESC

Guidelines

I - A

Medical Management (including oral antiproliferative agents)

Repeated PCI:

Balloon angioplasty (BA)

Non-compliant balloons

Cutting /Scoring balloons (CB)

Drug-Eluting Balloons (DEB)

Brachytherapy (VBT)

Rotational atherectomy / Laser

Bare-Metal Stents (BMS)

Drug-Eluting Stents (DES)

Homo-DES

Hetero-DES (Switch)

Coronary Surgery

Treatment of DES ISR:

Meta-Analyses on ISR

Author Date Patients/Trials Network

Metaanalysis

Interventions 1ry End-Point Main Result

(Better>Worse)

OR (95%CI)

Radke et al16 2003 3012/28 VBTvsBA MACE VBT>BA -37.7+4.0%*

Costantini et al17 2003 133 VBTvsPlacebo BR VBT>placebo 0.06 (0.02- 0.17)(+)

Uchida et al18 2006 1310/5 VBTvsPlacebo MACE VBT > placebo 0.19 (0.09-0.29)

Dibra et al19 2007 1230/4 DESvsVBT TLR DES>VBT 0.35 (0.25-0.49)

Oliver et al20 2008 3103/14 DESvsVBTvsBA MACE DES=VBT>BA 0.72 (0.61-0.85)

Alfonso et al21 2008 300/2 DESvsBMS BR DES>BMS 0.11 (0.03-0.36)(+)

Lu et al22 2011 1942/12 DESvsVBT TVR DES>VBT 0.44 (0.23-0.81)

Yu et al23 2013 349/5 DCBvsDES/BA TLR DCB>DES/BA 0.17 (0.07-0.38)

Navarese et al24 2013 399/4 DCBvsDES/BA TLR DCB>DES/BA 0.20 (0.11-0.36)

Indermuehle et al25 2014 801/5 DCBvsPES/BA MACE DCB>PES/BA 0.46 (0.31-0.70)

Sun et al26 2014 6330/28 DESvsOther TLR DES>BMS>other 0.46 (0.34-0.62)

Vyas et al27 2014 1680/10 SameDESvsDifDES TLR DES>DES 0.73 (0.45-0.93)

Piccolo et al 28 2014 1586/7 X DCBvsDESvsBA %DS DCB=DES>BA -17.7 (-25- -11)**

Mamuti et al29 2014 864/5 DCBvsDES/BA MACE DCB>DES>BA 0.49

Mamuti et al30 2015 803/4 DCBvsDES MACE DCB=DES 1.04

Li et al31 2015 1448/9 DCBvsDESvsBA MACE DCB=DES>BA 0.21 (0.13-0.33)

Benjo et al32 2015 1375/5 VBTvsDES TLR DES>VBT 2.4 (1.5-3.6)

Siontis et al33 2015 5923/27 X Multiple %DS EES>DCB>other -9 (-15.8- -2.2)**

Lee et al6 2015 2059/11 X DCBvsDESvsBA TLR DCB=DES>BA 0.22 (0.10-0.42)

%DS: Percent diameter stenosis; EES: Everolimus Eluting Stent; DCB: Drug Coated Balloon; VBT: Vascular Brachytherapy; TLR: Target Lesion revascularization; DES: Drug Eluting Stent; MACE:

Mayor Adverse Cardiac Events;DifDES: different (hetero) DES; SameDES: Similar (homo) DES; TVR: Target Lesion Revascularization. (+) Simple pooled analysis of randomized clinical trials. Other :

more than 2 different interventions. ; (*): Probability of MACE (in %)

(**): %DS

Alfonso F, Rivero F. J Thorac Dis 2015;7(10):1678-1683.

DCB

Late Loss

(mm)

(%)

PEB

BA

Habara S. J Am Coll Cardiol Intv 2011;4:149 –54

RCT: 50 Pts SES ISR

25 PEB vs 25 BA

(%) TLR

DCB in SES ISR

Restenosis

PEB for ISR (Acute)

D E F * * *

A B C * *

*

2/6/2011 RIBS IV (DB #52323, #1838961) Sandoval J, Alfonso F. J Invasive Cardiol. 2012 Oct;24(10):E215-8.

PEB for DES ISR (Follow-up)

D E F

* * *

* * *

A B C

2/6/2011 RIBS IV (DB #52323, #1838961) Sandoval J, Alfonso F. J Invasive Cardiol. 2012 Oct;24(10):E215-8.

Primary Endpoint: Diameter Stenosis at FU

Diameter Stenosis at Follow-up Angiography (%)

Cu

mu

lati

ve

Fre

qu

en

cy

(%

)

0 20 40 60 80 100

0

20

40

60

80

100

Balloon Angioplasty (BA)

Paclitaxel-Eluting Balloon (PEB)

Paclitaxel-Eluting Stent (PES)

PEB versus PES

Pnon-inferiority =0.007

PEB versus BA

PES versus BA

Psuperiority <0.001

PEB 38.0%

PES 37.4%

BA 54.1%

ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents

for In-Stent Restenosis: 3 Treatment Approaches

ISAR-DESIRE 3

ISAR-DESIRE 4: Primary Endpoint Diameter Stenosis at Follow-up Angiography

ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing

Treatment of Drug Eluting Stent In-Stent Restenosis 4

0 20 40 60 80 100

0

20

40

60

80

100

Diameter Stenosis at Follow-up Angiography (%)

Cu

mu

lati

ve

Fre

qu

en

cy

(%

)

Scoring-balloon

Control

P= 0.047

40.4% ± 21.4

35.0% ± 16.8

“Implications of a Third Metal Layer in

Human Coronary Arteries”

21 consecutive Pts Stenting for recurrent ISR after stenting for ISR

Alfonso F, et al. J Am Coll Cardiol 2009;53:2053-60

High Pressures 20+4 atm

(p<0.05 as compared with 2nd ST)

Angiographic Restenosis 21%

2nd ISR BA 3rd ST FU

DES Restenosis

Second vs First Gen DES

RIBS III (Rx DES ISR). Hetero-DES (Switch) 363 Pts DES ISR from 12 Spanish sites. 274 (75%) Hetero-DES vs 89 (25%) No Hetero-DES

Time (Years)

MACE (Cardiac death, MI, TLR)

Restenosis: 2nd Gener DES:

Total: 16 vs 31%, p=0.009

Any DES: 16 vs 28%, p=0.04

Hetero-DES: 15 vs 26%, p=0.08

Alfonso F et al. TCT 2011 Presentation (Featured Research)

309 Pts DES-ISR

Randomization

Inclusion Criteria

Informed Consent

Rx Centralized

Stratification:

ISR Length & Edge

154 Pts

DEB

155 Pts

EES

3 Died

12 Refused

139 Pts Angio FU

4 Died

18 Refused

133 Pts Angio FU Mean: 279 days

(Median: 248) Mean: 266 days

(Median: 246) (272 Patients: 90% of Eligible)

QCA Primary

End-point

100% Angiographic Success

SeQuent Please (B. Braun)

Xience Prime

(Abbott Vascular)

RIBS IV (Januray 2010 – August 2013)

RIBS IV

QCA: MLD at FU

0

0,5

1

1,5

2

2,5

0

0,5

1

1,5

2

2,5

MLD-FU DEB EES

Seg

p = 0.004

2.03 1.80

Lesion p < 0.001 (mm)

1.89 2.20

MLD-FU

(mm)

In-Segment (Primary Endpoint)

In-Lesion

Clinical Follow-up:

0 1 2 3 4 5 6 7 8 9 10 11 12

0

20

40

60

80

100 %

Time (months)

Freedom from TLR

__

EES __ DEB

1 Year FU 309 P (100%); FU Time 360+35 days

Breslow, p = 0.008

Log Rank, p = 0.008

96%

87%

RIBS IV

BVS for DES ISR

A

B C D E

* *

* *

+

+ + +

+

+

^ ^

F G H I

*

* * *

Absorb for ISR Alfonso F, et al J Am Coll Cardiol 2014:63:2875

BVS for ISR

RIBS VI

BVS for ISR

Multicenter Prospective Study

Mandated Angio FU

141 Patients

2016

Alfonso F, et al TCT 2016

RIBS VI

TCT 2016

Flow Diagram

Same RIBS Centers

Incl/Excl / Criteria

Informed Consent

RIBS VI Prospective, Angio FU

(BMS-ISR and DES-ISR)

141 9Mo (100%); 124 (88%) 1Y (17 Pending)

QCA

(95% of Eligible)

Primary End-point

134 Pts Angio FU

498 Pts ISR

309 Pts RIBS IV; 189 Pts RIBS V

Randomization

249 Pts

EES

249 Pts

DEB

219 Pts Angio FU

223 Pts Angio FU Mean: 257 days

Mean: 270 days

100% Angio Success

SeQuent Please (B. Braun)

Xience Prime

(Abbott Vascular)

498 1Y Clinical FU (100%)

442 Pts: 91% of Eligible

QCA Primary End-point

January 2010

August 2013

141 Pts

BVS Absorb

(Abbott Vascular)

100% Angio Success

April 2014

December 2015

ClinicalTrials.gov Identifier: NCT01239953 & NCT01239940

Alfonso F, et al TCT 2016

Algorithm for DES ISR Treatment

DES ISR

Medical Rx

FFR (IVUS/OCT)

(-)

Asymptomatic

Severity ?

IVUS / OCT

Underlying Mechanism

DES

DES

DES

Focal

Gap

Fracture

Edge

Body

Diffuse

Underexpansion ?

Optimization

Pressure NC BA

Avoid Geo Miss

DES / DEB

Prefered DES: Hetero DES & 2nd G

Favor DEB: Multiple ST layers, major SB

Muchas Gracias

Fernando Alfonso MD, PhD, FESC

Department of Cardiology

Hospital Universitario de La Princesa.

Madrid. Spain

XXXI Jornadas SOLACI. 10ª Región CONOSUR

LIIIº Congreso Chileno de Cardiología y Cirugía Cardiovascular