Fernando alfonso isr sec-2015

Avances en Cardiología IntervencionistaSección de Hemodinámica y Cardiología Intervencionista.

Tratamiento de la Reestenosis Intra-Stent:

Cual es el Mejor Tratamiento?

Fernando Alfonso Hospital Universitario de La Princesa

UAM. Madrid.

Cursos Casa del CorazónSEC

Jueves 17 Septiembre 2015

Restenosis “Activity”

Baz A, et al. Rev Esp Cardiol 2008;61:1298-314

2007 Official Spanish Registry(Working Group on Hemodynamics and Coronary Interventions)

60,457 Procedures(94.5%) De Novo

3,277 (5.5%)Restenosis

En el 2012 la reestenosis representó el 4,9% de los casos (el 5% en 2011 y el 5,3% en 2010), y se aprecia

una tendencia a la disminución.

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

112 (9.5%)

ISR: Clinical Presentation

Chen M, et al. Am Heart J 2006;151:1260-1264

1,186 Patients BMS ISR

313 (26.4%) 761 (64.1%)

MI UA

SA

Treatment of DES ISR:

Pattern I: 19%Pattern II: 34%Pattern III: 50%Pattern IV: 83%

TLR 1 Y

Mehran R, Circulation. 1999;100:1872-1878.)

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:

Medical Management (including oral antiproliferative agents)

Repeated PCI: Balloon angioplasty (BA) Non-compliant balloons Cutting /Scoring balloons (CB) Drug-Eluting Ballons (DEB) Brachytherapy (VBT) Rotational atherectomy / Laser Bare-Metal Stents (BMS) Drug-Eluting Stents (DES)

Homo-DES Hetero-DES (Switch)

Coronary Surgery

Treatment of ISR:

IVUS Severe Underexpansion

AMLA & EEL

B “Sand Glass”

DES Restenosis

Calcified DES ISRA

+ +

+

+

+

+

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.

Treatment of In-Stent RestenosisBalloon Angioplasty

Alfonso F, et al Am J Cardiol 1999;83:1268-70

RIBS: 125BD: 5114

MLD: QCA

1.1 mm

Intravascular UltrasoundImmediate Recoil After Ballon PTCA for ISR

3.0x12 Bar2 mm

20’1,4 mm

Angiographic Results: MLD

%100

80

60

40

20

00 0.5 1.0 1.5 2.0 2.5 3.0 3.5

MLD (mm)

baseline

PTCAROTA

post interv.6 month

RE51%65%

% Stenosis Post 1y TVR

In-ST RE "The Great Equalizer"

Malhotra S et al, JACC 1999:62A.

821 Pts In-ST-RE Washington Hospital Center

ANOVA * p<0.05

2117

22

10

2731

2327

PTCA 314 ELCA 250 RA 126 ST 13105

101520253035

(%)

*

Baseline Demographics Similar Among Groups

Holmes DR, et al. JAMA 2006;295;1264-73

SES vs Brachytherapy

TVF = Cardiac Death, MI, TVR at 9 Mo

(%)

*

Primary End Point: Target Vessel Failure (TVF) : (RR 1.7, 95%CI 1.1 – 2.8)

12,4

21,6

0

5

10

15

20

25

SES

VBT

p<0.05*

MLD FU: 1.8+0.6 vs 1.52+0.6 mm, p<0.001

SISR (Sirolimus-Eluting Stent for In-Stent Restenosis Trial). 384 Pts (125 Brachy, 259 SES)

10 Pre-Specified Variables:RIBS

RR (95% CI)ST Better BA Better

Restenosis

Age >65y

Female

Diabetes

UA

Time RE (> 6Mo)

LAD

RE Length (>10mm)

ST # 1 Coil

B/A > 1.10.1 1Log RR

0.55 (0.35-0.85)p=0.007

4 Pts treated prevent 1 RE

Vessel QCA (> 3mm)

450 P with ISR

RIBS

“WMS” 42 P (9%)

No WMS 408 P (91%) “WMS” on “Complications” at the

(Case Report Form). Detailed “Drawings” required.

Material scrutinized. Detailed Analysis of every balloon

inflation (all filmed by protocol requirement).

Centralized Review at the angiographic “Core-Lab”.

“Watermelon Seeding” Phenomenon

More severe and diffuse ISR More inflations & longer time Never during “stent deployment” Cross-over or residual dissections Poorer Acute and Long-term

Angiographic Results

1 2 3

Gomez-Recio M, New Orleans ACC 2004

RESCUT

25

7

0

5

10

15

20

25

30

Slippage (%)

BA CBA* p<0.05

*31 30

0

5

10

15

20

25

30

35(%)

Restenosis(%)

1516

02468

1012141618

MACE

MACE: Death, MI, TLRAlbiero R, et al. J Am Coll Cardiol 2004;43:943-949

Restenosis Cutting Balloon Evaluation Trial

450 P with ISR

RIBS

“EDG” ISR 52 P (12%)

No EDG ISR 398 P (88%) “EDG” ISR “Predefined” by

protocol (Case Report Form). “Detailed Drawings” required.

ISR RIBS (>3 mm or >25% RE length: intra-ST).

Centralized Review at the angiographic “Core-Lab”.

“EDG” ISR

More benign CRF profile Shorter and less severe lesions Higher cross-over requirement Similar Clinical & Angio outcome

Angel J, et al. Circulation 2002;106:II-481.

ST

EDG ISR

RIBS

1 Year Clinical FU 1,0

,9

,8

,7

,6

,5

12 11 10 9 8 7 6543210

Time (months)

(Freedom from Death, MI, TVR)__ BA __ ST

Log Rank p = 0.01

52%

83%

Breslow p = 0.008

“EDG” ISR

Angel J, et al. Circulation 2002;106:II-481.

1st STEDGISR

Where Are DCB Useful Today?

¨ ISR (BMS & DES)¨ De novo Lesions:

¨ Bifurcation (DEBUIT, PEPCAD V, BABILON)

¨ Small vessels (PEPCAD I, PICOLLETO, BELLO, RAMSES)

¨ Difusse disease (STARDUST)

¨ Diabetics (PEPCAD IV)

¨ AMI (DEB-AMI, PEPSI, PAPPA)

¨ CTO (PEPCAD CTO)

(Combined with BMS : before or after)

Scheller B, et al. N Engl J Med 2006;355;2113-24

DCB in BMS ISR

Late Loss

Restenosis Rate

(mm)

(%)

P-BA

BA

DCB vs PES in BMS ISR

Unverdoben M et al , Circulation 2009:119(23):2986-94

0,17

0,38

0

0,05

0,1

0,15

0,2

0,25

0,3

0,35

0,4

Late Loss(mm)

MLD Event Free Survival

p=0.03 FU 2.03 vs 1.96, p=0.60 p=0.08

P-BA PES

Late Loss

(mm)

(%)

PEB

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

RCT: 50 Pts SES ISR25 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.

ISAR-DESIRE 3

DesignDESIGN: Prospective, randomized, active controlled, multicenter clinical trial

INCLUSION CRITERIA: 1. Stenosis > 50% in “limus”-eluting DES2. Symptoms/signs of ischemia

EXCLUSION CRITERIA: 3. Lesion in left main stem4. Acute STEMI5. Cardiogenic shock

SPONSOR: Deutsches Herzzentrum

ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches

402 patients with DES-restenosis enrolled between August 2009 and October 2011 in 3

centers in Germany

Angiographic follow-up at 6-8 months in 84.1% (N=338)

Clinical follow-up at 12 months in 97.5% (N=392)

Paclitaxel-eluting stent

(Taxus)(N=131)

Balloon angioplasty

alone(N=134)

Paclitaxel-eluting balloon

(SeQuent) (N=137)

No significant differences across groupsRobert A. Byrne

Primary Endpoint: Diameter Stenosis at FU

Diameter Stenosis at Follow-up Angiography (%)

Cum

ulat

ive

Freq

uenc

y (%

)

0 20 40 60 80 1000

20

40

60

80

100

Balloon Angioplasty (BA)

Paclitaxel-Eluting Balloon (PEB)Paclitaxel-Eluting Stent (PES)

PEB versus PESPnon-inferiority =0.007

PEB versus BAPES versus BAPsuperiority <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

Secondary EndpointBinary Restenosis

P = .61

ISAR-DESIRE 3: Intracoronary Stenting and Angiographic Results: Drug Eluting Stents for In-Stent Restenosis: 3 Treatment Approaches

P = .09

PEB versus BAPES versus BA

P <0.001

PEB versus BAPES versus BA

P <0.001

Target Lesion Revascularization

PEB BAPESPEB BAPES

% %

ISAR-DESIRE 4 Trial DesignDesign

DESIGN: Prospective, randomized, active controlled, multicenter clinical trial

INCLUSION CRITERIA: 1. Stenosis >50% in “limus”-DES2. Symptoms/signs of ischemia

PRIMARY ENDPOINT: Percentage diameter stenosis at follow-up angiography

Planned Enrollment250 patients

Scoring balloon(Angiosculpt)

+Paclitaxel-

eluting balloon(Pantera Lux)

Paclitaxel-eluting balloon

(Pantera Lux)

ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Drug Eluting Balloons for In-Stent Restenosis 4

DEB for Patients with DES ISR

• By removing the need for an additional stent layer, DEB might become the treatment of choice for patients with DES ISR.

• Nevertheless, information about the relative efficacy of DEB vs second-generation DES in these patients is needed. Studies addressing this question are underway (RIBS V & IV).

• So far, treatment of ISR has been perceived as an endless and largely fruitless research effort.

• DEB have changed the treatment of patients with DES ISRAlfonso F, Pérez-Vizcayno MJ. Lancet. 2013 Feb 9;381(9865):431-3.

Windeker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014 Aug 29. pii: ehu278.

New ESC Guidelines on Revascularization

Windeker S, Kolh P, Alfonso F, et al. Eur Heart J. 2014 Aug 29. pii: ehu278.

New ESC Guidelines on Revascularization

DEB for BMS-ISR or DES-ISR (I A)

A “class effect” of DEB has not been demonstrated

Long-Term (5 Years) Safety and Efficacy of DCB

TLR , MI, stroke, death

Scheller B, et al. JACC CV Interv 2012;5:323-30.

Safety of DCB at 2 years

220 Pts DES-ISR (DCB vs PES)PEPCAD China ISR

TCT 2014. JACC Vol 64/11/Suppl B; September 13–17, 2014

Safety of DCB at 3 years

ISAR-DESIRE III (DCB vs PES vs BA)3 years FU

• At a median follow-up of 3 years, the risk of TLR was comparable with PEB versus PES (HR: 1.46, 95% CI, 0.91-2.33; P=0.11) and lower with PEB versus BA (HR: 0.51, 95% CI,0.34-0.74; P<0.001).

• The risk of death/MI tended to be lower with PEB versus PES (HR: 0.55, 95% CI, 0.28-1.07; P=0.08), due to a lower risk of death (HR: 0.38, 95% CI, 0.17–0.87; P=0.02).

Kufner JACC Cardiovasc Interv 2015 Jun;8(7):877-84.

DEB for Patients with DES ISR

Alfonso F, Cuesta J. JACC Cardiovasc Interv. 2015 Jun;8(7):885-8.

The current study by Kufner et al. confirms the1) safety 2) durable antirestenotic efficacy Of DCB for DES-ISR: results similar to 1st-Gen DES (PES).…. 2nd Gen DES?

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)

“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

RIBS V

189 Pts BMS ISRRandomization

Inclusion CriteriaInformed Consent

Rx CentralizedStratification: ISR Length & Edge

95 PtsDEB

94 PtsEES

3 Died1 Thrombosis7 Refused

84 PtsAngio FU

8 Refused

86 PtsAngio FU Mean: 270 days Mean: 271 days

(170 Patients: 92% of Eligible)

QCAPrimary

End-point

100% Angiographic Success

SeQuent Please (B. Braun Surgical)

Xience Prime(Abbott Vascular)

(January 2010 to January 2012)

RIBS V1ry Endpoint: MLD at FU

0

0,5

1

1,5

2

2,5

0

0,5

1

1,5

2

2,5

SegLesion

p < 0.0001

(mm)

2.032.44

MLD-FU

MLD-FU DEBEES

p < 0.0001

2.36 2.01

(mm)

In-Segment

In-LesionAdjusted (age, smoker, stenosis, diabetes) p = 0.001

Cumulative Frequency Distribution CurvesRIBS V

(%) StenosisIn-Segment Intention to Treat

-20 -10 0 10 20 30 40 50 60 70 80 90 100

__ DEB __ EES

0

20

PRE

40

60

80

(%)100

p < 0.001FU

RE4 (4.7%)8 (9.5%)p = 0.22

POSTp < 0.001

0

RIBS VClinical Follow-up:

0 1 2 3 4 5 6 7 8 9 10 11 120

20

40

60

80

100%

Time (months)

Freedom from MACE (Cardiac Death, MI, TVR)

__

EES__ DEB

1 Year FU 189 P (100%); FU Time 361+28 days

Breslow, p = 0.65Log Rank, p = 0.60

94%

91%

309 Pts DES-ISRRandomization

Inclusion CriteriaInformed Consent

Rx CentralizedStratification: ISR Length & Edge

154 PtsDEB

155 PtsEES

3 Died12 Refused

139 PtsAngio FU

4 Died 18 Refused

133 PtsAngio FU Mean: 279 days

(Median: 248) Mean: 266 days

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

QCAPrimary

End-point

100% Angiographic Success

SeQuent Please (B. Braun)

Xience Prime(Abbott Vascular)

RIBS IV(Januray 2010 – August 2013)

QCA: MLD at FU

0

0,5

1

1,5

2

2,5

0

0,5

1

1,5

2

2,5

MLD-FU DEBEES

Seg

p = 0.004

2.03 1.80

Lesionp < 0.001 (mm)

1.892.20

MLD-FU

(mm)

In-Segment(Primary Endpoint)

In-Lesion

RIBS IV

Cumulative Frequency Distribution Curves

(%) StenosisIn-Segment Intention to Treat

(%)

0

20

40

60

80

100

-20 -10 0 10 20 30 40 50 60 70 80 90 100

PREPOSTp < 0.001

p = 0.009

__ DEB __ EES

RE15 (11%)27 (19%)p = 0.06

RR (95%CI) 1.44 (0.94-2.20)

FU

RIBS IV

Clinical Follow-up:

0 1 2 3 4 5 6 7 8 9 10 11 120

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 = 0.008Log Rank, p = 0.008

96%

87%

RIBS IV

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

DEB vs BA in the RIBS Trials

Late Loss

DEB RIBS IV

0.14+0.5

0.77+0.7 p < 0.05

(QCA) In-Segment Analysis

DEB RIBS V0

0,5

1

1,5

2

2,5

MLD FU(mm)(mm)

BA RIBS I BA RIBS II

1.52+0.7

2.01+0.6

1.52+0.7

0.73+0.7p < 0.01

BA RIBS I BA RIBS II DEB RIBS IVDEB RIBS V

1.80+0.6

0.30+0.6

RIBS IV

BMS-ISR BMS-ISRDES-ISR DES-ISR

DES Restenosis

58% Rupture, 52% TCFA, 58% Thrombus

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

Rupture TCFA

TCFAThrombus

OCT in 50 Pts with DES ISR

A B

C D +

+

+*

*

*

*

Neoatherosclerois After Paclitaxel-Eluting BalloonPEB for DES ISR

Alfonso F, et al. Circulation 2014;129:923-5.

“The elusive link between very late ISR and ST”Ruptured Neoatherosclerosis

B *

PRESTIGE (13/08/2012)

E

*

+

+

+

D

*

+

+

+

A

BCDE *

T

C

DES Restenosis

Alfonso F, et al. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt A):2875.

B

D

C

E*

+*

*

*

**

T

++

+

+

+

+

A

Neoatherosclerosis Causing Late STDES Restenosis

T

NCA B

Neoatherosclerosis Causing Late ST

DES Restenosis

(Jimenez-Quevedo P HCSC)

Meta-analysis on ISRAuthor Date Patients/Trials Network

MetaanalysisInterventions 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. In press.

Sointis GT, et al Lancet. 2015 Aug 15;386(9994):655-64.

Percutaneous coronary interventional strategies for treatment of in-stent restenosis: a network meta-analysis.

“Network” Meta-analysis

27 trials eligible, including 5,923 patients• EES was the most effective treatment for % diameter

stenosis, with a difference of:-9.0% vs DCB

-9.4% vs SES-10.2% vs PES -19.2% vs brachytherapy, -23.4% vs BMS -24.2% vs BA, -31.8% vs rotablation.

• DCB were ranked as the second most effective treatment, but without significant differences from SES or PES

DES RestenosisA

B C D E

**

**

+

+ + ++

+

^^

F G H I

*

** *

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

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 ?

2nd DES / PEB

Optimization

Pressure NC BA

Cutting/Scoring (?)

Avoid Geo Miss

Prefered DES: Hetero & 2nd G Favor PEB: Multiple ST layers, major SB