PCI for Lesion with In-stent Restenosis restenosis.pdfPCI for Lesion with In-stent Restenosis. ... Therapy for In-Stent Restenosis: AMC Experience. Cardiovascular Research Foundation

Cardiovascular Research Foundation ANGIOPLASTY SUMMIT

PCI for Lesion with In-stent Restenosis


The history of angioplasty The history of angioplasty is is ……

… The history of response to Restenosis


An Evolutionary Process of PCIAn Evolutionary Process of PCI

1977 – 1988 Balloon Angioplasty

1988 – 1993 New Device Angioplasty

1993 – Stent Era

1997 – Vascular brachytherapy2001 – Drug-Eluting Stent


Balloon Angioplasty & Balloon Angioplasty & RestenosisRestenosis

NeointimalNeointimal hyperplasiahyperplasia

Recoil and remodelingRecoil and remodeling


Intervention 2003Intervention 2003

0%

20%

40%

60%

80%

100%

1997 1998 1999 2000 2001 2002

Stents Balloon Angioplasty Atherectomy

49

25

70

45

1749

848049

13

86

12

In-Stent Restenosisis the most serious problem

(20-25%)


“ The dream ”of interventional cardiology will be …

No Restenosis !


Solution• Stents will prevent vascular recoil and

remodeling• Active therapeutic agent is required to

block neointimal hyperplasia

CauseRecoil and remodeling Neointimal hyperplasia

RestenosisRestenosisRestenosis


Treatment of Diffuse ISRTreatment of Diffuse ISREffective Treatment Tools?Effective Treatment Tools?

•Intracoronary Brachytherapy

•Drug-eluting stent

Intracoronary Brachytherapy


Mechanism of Mechanism of Radiation

Prevent Restenosis

• Target : Adventitial myofibroblast

• Inhibition of neointima and negative remodeling


BrachytherapyReported Clinical Trials for ISRTRIAL

SCRIPPSWRISTGAMMA 1GAMMA 2LONG WRISTB-WRISTSTARTINHIBITBRITE

Sourse

192Ir192Ir192Ir192Ir192Ir90YSr/90P32P32

Length(mm)15.323.720.21932

20.6171717

Pts(n)351302521251205047633226

Placebo70.558.350.5

71

42.248

Treated11.119

21.6233222

14.2160

Restenosis Restenosis %%


Brachytherapy to Treat ISRReduction of Re-ISR

0

10

20

30

40

50

60

70

80

LongWRIST

WRISTGAMMA-1

SCRIPPSINHIBIT

STARTCon

Ir192Con

Ir192Con

Ir192Con

Ir192Con

P32Con

Sr/Y90

71

32

61

22

56

33

54

17

5245

29

36%50%64%41%64%

55%

26

%γ radiationβ radiation


Vascular BrachytherapyVascular BrachytherapyCurrent Status

• Randomized trials showed a 35-70% reduction in the recurrence rate of instent restenosis

• The Late thrombosis phenomenon reported to resolved with prolonged antiplatelet therapy (WRIST PLUS, SCRIPPS III, START, INHIBIT)

What We need As a Pretreatment

Before Brachytherapy ?

Simple Balloon.Rotablation.

Cutting Balloon.


188Re-MAG3 - Beta Radiation

• Rapid fall-off radiation dose within 2 mm • The increased chance of inhomogeneous

dose delivery to target tissue (esp. eccentric plaque)

Role of Rotablation


Rotational Atherectomybefore Beta Radiation

Produce concentric and thinner neointima structure ; Radiation dose can be homogeneously delivered to target tissue


AMC ExperienceR4 Trial

Radiation with188Re-MAG3-filled balloon afterRotablation for diffuse in-stentRestenosis

SW Park, et al. JACC 2001:38:631-7


Inclusion Criteria

•Diffuse In-stent Restenosis(>10mm in length)

•Total occlusion



Subject

From March 1999 to May 2001From March 1999 to May 2001

103 patients (57 yrs, M/F: 80/20) Diffuse ISR (mean lesion length 24.1+21.9 mm)



Design

First 50 consecutive First 50 consecutive patients have been patients have been performed performed rotablationrotablationprior to radiation, prior to radiation,

and the remaining 53 and the remaining 53 consecutive patients consecutive patients received balloon + received balloon + radiation strategy. radiation strategy.

• Rota+RTN=50

• Balloon+RTN=53



Lesion Length

Rota +RT Balloon +RT(n=50) (n=53)

Mean Lesion Length 25.6±12.7 22.9±8.8 (mm)

>10,<20 (mm) 21(42) 20(38) >20,<30 13(26) 23(43)>30 16(32) 10(19)

*Total occlusion 10(20) 5(10)SW Park, et al. JACC 2001:38:631-7


Minimal Lumen Diameter

Rota+RT Balloon+RT(n=50) (n=53) p-value

Baseline (mm) 0.60 ± 0.44 0.70 ± 0.37 0.159Final 2.68 ± 0.39 2.61 ± 0.44 0.355Follow-up 2.31 ± 0.60 1.94 ± 1.00 0.004*

Acute gain 2.08 ± 0.46 1.91 ± 0.48 0.875Late Loss 0.36 ± 0.64 0.66 ± 1.20 0.001*Loss index 0.17 ± 3.10 0.45 ± 0.57 0.001*



Immediate Results


100 86

6 (12%)1 (2 %)00

100 100

0 000

Clinical Success(%)Procedural Success(%)New Stent due to;

Edge dissection Intramural Hematoma

Major complicationIsotope leakage



6-month angiographic F/U


6 month angiographicF/U (%)

Restenosis Rate (%)

InstentEdge

50/50 (100) 5/50 (10%)

41

51/53 (98)17/51 (34%)

125



6-month angiographicRestenosis Rate & TLR

(%)

0

10

20

30

40

50

Rota + RT Balloon + RT

RestenosisTLR

104

34

16

P=0.004P=0.060

1/50

8/53

17/51

5/50


2 2 yearyear Clinical FollowClinical Follow--UpUpRota +RT Balloon +RT

(n=50) (n=50)

17/50 (34%)5 (10%)8/50 (16%)

3111110

5/50 (10%)2 (4%)2 (4%)

0110

1 (2%),Non-cardiac

Restenosis Rate (%)Symptom RecurrenceTLR (%)

PTCAStent CABGRotablationRTCutting balloon

DeathSW Park, et al. JACC 2001


Survival CurveSurvival Curve

Follow-up duration (months)0 6 12 18 24

Perc

enta

ge

0

70

80

90

100100%

P=NS98.0 ± 0.2%

27.1±5.87 moRota + RT14.1±5.96 moBalloon +RT



TLRTLR--free Survival Curvefree Survival Curve98.0 ± 0.2%

P = 0.046

0 6 12 18 24

Perc

enta

ge

70

80

90

100

84.8 ± 5.0%

27.1±5.87 moRota + RT14.1±5.96 moBalloon+RT

0

Follow-up duration (months)SW Park, et al. JACC 2001:38:631-7


MACEMACE--free Survival Curvefree Survival Curve

Follow-up duration (months)0 6 12 18 24

0

95.9 ± 2.9%

P = 0.040

Perc

enta

ge

70

80

90

100

84.1 ± 5.2%

27.1±5.87 moRota + RT14.1±5.96 moBalloon+RT



Conclusion

• Intracoronary brachytherapy using 188Re -MAG3 liquid filled balloon system for diffuse ISR is safe and feasible and, effective to prevent recurrent ISR

• Debulking using Rotablation prior to radiation seemed to be beneficial to the late clinical outcomes in restenosis rate and TLR.


Role of Cutting Balloon


Role of Cutting BalloonWithout Brachytherapy

RESCUT

Lesion characteristics

62.430.8Diffuse/Proliferative18.846.1Multifocal18.823.1Focal16.4%13.3 %> 20 mm single/multiple40.531.8Diffuse/Proliferative17.212.9Multifocal42.355.3Focal

0.4483.6%86.7 %≤ 20 mm single stent

P valuePTCA(n=237)

CB(n=229)


Role of Cutting BalloonWithout Brachytherapy RESCUT

Binary Restenosis

0

10

20

30

(%)

CBT(n=229)

29.8% 31.3%

P=0.82

PTCA(n=237)


Role of Cutting BalloonWithout Brachytherapy RESCUT

Balloon slippage

0

5

10

15

20

25

30(%)

CBT(n=229)

6.5%

25.1%

P<0.01

PTCA(n=237)

0

5

10(%)

CBT(n=229)

3.9%8.0%

P=0.07

Additional stenting

PTCA(n=237)


RENO Registry (n=1111)Cutting Balloon before Brachyehrapy

6 Month MACE

0

5

10

15

20(%)

Balloon + RT(n=722)

19.2%

10.8%

P=0.01

CBA + RT(n=166)


Cutting Balloon Angioplasty Vs.Rotational AtherectomyPerformed Before Beta Radiation Therapy for In-Stent Restenosis:

AMC Experience


Cutting Balloon or Rotablation before RTx

0.031.17 ± 0.191.10 ± 0.16Balloon/Artery ratio

0.7221.6 ± 10.321.0 ± 10.2Lesion length, mm

0.602.88 ± 0.482.92 ± 0.40Ref artery size,mm

Cutting + RT(n=69)

2.02 ±0.210.70 ± 0.12

4.8 ±2.5

Rotablation Burr size(mm) Burr/Artery ratioFrequency

p-valueRota + RT (n=70)


Subject

139 patients (M/F: 89/50, 59 yrs)

Diffuse ISR (mean lesion length 20.3±8.9 mm)


DesignIn-Stent Restenosis

(N=139)

RandomizationRandomization

Rota + RTN=70

Cutting + RTN=69


Procedure-related Data

0.031.17 ± 0.191.10 ± 0.16Balloon/Artery ratio

0.7221.6 ± 10.321.0 ± 10.2Lesion length, mm

0.602.88 ± 0.482.92 ± 0.40Ref artery size,mm

Cutting + RT(n=69)

2.02 ±0.210.70 ± 0.12

4.8 ±2.5

Rotablation Burr size(mm) Burr/Artery ratioFrequency

p-valueRota + RT (n=70)


Procedure-related Data

0.27 0.22

71.4 ± 13.8 6.0 ± 17.3

74.0 ± 13.29.2 ± 12.9

Diameter stenosis BaselineFinal

0.215.7 ± 1.86.1 ± 2.2Pressure (atm)

0.35 0.50

0.83 ± 0.402.68 ± 0.50

0.76 ± 0.40 2.63 ± 0.40

MLD, mmBaselineFinal

Cutting + RT(n=69) p-valueRota + RT

(n=70)


Radiation Coverage

27 (39%)32 (46%)8 (12%)2 (3%)

17 (24%)42 (60%)10 (14%)1 (1%)

≤ 30 mm30< ≤40 mm60 mm (overlap)80 mm (overlap)

0.69185±87191±86RT Time (sec)

0.4138.7±12.040.3±11.0Radiation Balloon Length (mm)

Cutting + RT(n=69)

p-value

Rota + RT (n=70)


Immediate Results

00

00

Major complicationIsotope leakage

3 (4%)7 (10%)New Stent due to

Edge dissection

100 100Success rate (%)

Cutting + RT(n=69)

Rota + RT (n=70)


6-Month Angiographic F/U

• Eligible 101 patients • Angiographic follow-up rate = 76% (77/101)

- Rota + RT (69%, 35/51)

- Cutting + RT (84%, 42/50)


6-Month Angiographic F/U

0.86±0.37 2.73±0.40 1.82±0.85

0.77±0.412.57±0.43 1.74±0.71

Pre MLD (mm)Post MLD (mm)F/U MLD (mm)

Rota + RT (n=35)

0.330.100.66

p-value

Cutting + RT (n=42)

Acute gain (mm)Late loss (mm)Loss index

1.74±0.49 0.84±0.83 0.44±0.48

1.87±0.42 0.91±0.79 0.53±0.47

0.210.680.45


Restenosis Rate

0

10

20

30

40(%)

Cutting + RT Rota + RT

29 %(10/35)

36%(15/42)

P=0.51


8-months TLR Rate

0

5

10

15

20(%)

Cutting + RT Rota + RT

13%(9/69)

P=0.08

4%(3/70)


Conclusion

The cutting balloon angioplasty and rotational

atherectomy before brachytherapy using 188Re-MAG3 filled balloon showed similar

favorable acute and long-term outcomes.


Brachytherapy Durable effect ?


WRIST-Five year F/U (MACE)Freedom from death, MI , TLR

1.0P<0.002 Iridium

Prob

abili

ty

0.2

0.4

0.6

0.8 Placebo

0 3 6 9 12 24 36 48 60MACE Time in (Months)


SCRIPPS-Late Catch-Up

0

10

20

30

40

50

60

70(%)

Placebon=28

54%

192 Irn=24

Placebon=22

192 Irn=21

64%

17%

33%

6-Month Follow-UP 3-Year Follow-UPLate catch-up (n=4)

P=0.01

P<0.0569%48%


SCRIPPS-3 Years TLR

0

10

20

30

40

50

60(%)

Placebon=29

44.8%

192 Irn=26

Placebon=29

192 Irn=26

48.3%

11.5% 33%

6-Month Follow-UP 3-Year Follow-UP

P=0.01P<0.01

74%68%


SCRIPPS-Five year F/U (MACE)Freedom from death, MI , TLR

Prob

abili

ty

0.4

0.6

0.8

1.0

P=0.03

Treatment0.2

Placebo

0 12 24 36 48 60 72Time (Months)


TwoTwo--YearYear Angiographic Angiographic FollowFollow--Up In Up In Rota Rota + RT Group+ RT Group

AMC Experience


66--month & 2month & 2--yr yr angiographicangiographic FUFU

Total pts (n=50)

6-month FU50/50 (100%)

2-year FU26/45 (58%)

2 TLRs 5 Restenoses((RestenosisRestenosis=10%)=10%) 3 medicals

Patent (N=45)Patent (N=45)

4 late TLRs 6 late “catch-up”(Restenosis=23%) 2 medicals


6-month & 2-year angiographicRestenosis Rate

0

10

20

30

6-month 2-year

(%)

N = 50 patientsFU = 50/50 (100%)

N = 45 patientsFU = 26/45 (58%)

10%(5/50)

23%(6/26)


2-year angiographicRestenosis & TLR Pattern

• Focal 2Intrastent 1 1 Cutting balloonEdge 1 1 Medical

• Diffuse 4Intra-stent 1 1 MedicalTotal occlusion 3 2 Cutting balloons

1 CABG


66--month & 2month & 2--yr yr angiographicangiographic MLDMLD

0

1

2

3

4MLD(mm)

Postprocedural 6-month 2-year

2.682.31

1.81

P=0.018P=0.018P=0.011P=0.011

P<0.001P<0.001


66--month & 2month & 2--year IVUS Datayear IVUS Data

0

2

4

6

8

10

Ave

rage

CSA

(mm

2 )


8.29 8.27 8.28

6.45 6.28 5.80

1.84 1.99 2.49

P=0.49P=0.49 P=0.73P=0.73

P=0.003P=0.003P=0.26P=0.26

P=0.003P=0.003P=0.32P=0.32

Stent Stent CSACSA

Lumen Lumen CSACSA

IH IH CSACSA



0

4

8

12

16

20

Ave

rage

CSA

(mm

2 )


16.3 16.5 16.2

9.0 9.4 9.1

7.3 7.1 7.0

P=0.25P=0.25 P=0.22P=0.22

P=0.26P=0.26

P=0.36P=0.36

EEM EEM CSACSA

Lumen Lumen CSACSAP+MP+MCSACSA

P=0.36P=0.36

P=0.86P=0.86

Proximal reference segment



0

4

8

12

Ave

rage

CSA

(mm

2 )


10.0 10.7 10.1

5.6 6.0 5.4

4.4 4.7 4.6

P=0.06P=0.06 P=0.03P=0.03

P=0.27P=0.27

P=0.21P=0.21

EEM EEM CSACSA

Lumen Lumen CSACSAP+MP+MCSACSA

Distal reference segment

P=0.03P=0.03

P=0.89P=0.89


EventEvent--free Survival free Survival

0 6 12 18 24 30

Death-free Survival 98.0 ± 2.0%

MACE-free Survival 86.9 ± 5.0%Late

Catch-up

100

70

80

90

Perc

enta

ge

Mean follow-up duration = 32.2±4.5 months0

Follow-up duration (months)


Conclusion

•• BetaBeta--irradiation using a irradiation using a 188188ReRe--MAGMAG33--filled filled balloon after rotational balloon after rotational atherectomyatherectomy is safe is safe and feasible in patients with diffuse ISR. and feasible in patients with diffuse ISR.

•• LongLong--term term angiographicangiographic and clinical outcome and clinical outcome appears favorable for this highly appears favorable for this highly restenosisrestenosisprone group.prone group.

• However, late “catch-up” phenomena were observed in some patients after brachytherapy.


Drug-Eluting Stent forIn-Stent Restenosis

Safe and efficacious ?


Paclitaxel Stent for ISRPilot Study (n=21 pts)

Re-Restenosis

9 pts with optimal coverage

12 pts with a mismatch between the injured zone and the paclitaxel stent

0 / 9 pts

3 / 12 pts

Overall : 14%

De Scheerder IK, TCT


TAXUS III for ISR(N=27)

10 (35.8%)Focal

13 (46.4%)Diffuse

4 (14.3%)Proliferative

1 (3.6%)Total occlusion


TAXUS III -MACE

8 (29%)06-Month MACE1 (3.6%)0CABG

6 (21.4%)0TLR1 (3.6%)1 (3.6%)Non Q-Wave MI

00Q-Wave MI00Death

6 month30 day


TAXUS III for ISR2 Clinical Centers (n=28 pts)

Re-Restenosis = 4 / 25 (16%)

Post0

10

20

30

40%

13.917.4 19.3

14.3

30.8

14.8

6 Mos

Proximal In-Stent Distal

K Tanabe, Circulation 2003;107

Percent diameter stenosis


TAXUS III for ISRCharacteristics of TLR Patients

TLR6 Patients

2 Patients

Gap betweenTwo NIRx

Stents :

Geographic Miss

1 Patients

Restenosis in Bare stent next

To 2 NIRx

Mismatch

True Restenosis

2 Patients

TLR driven byIVUS showing

Incompleteexpansion

1 Patients

Anginal complains And smallMLD but

% DS > 50%


TAXUS III for ISRRestenosis Pattern

16 % (4/25)0% (0/13) 33% (4/12)

4.5 % (1/22)

Restenosis rateSingle stentMultiple stents

Subanalysis excluding mismatch and GM


Sirolimus-coated Stent for ISRSirolimus-coated Stent for ISR

Focal

Diffuse

Proliferative

Total occlusion

10 (40%)

Brazil (n=25)

3 (19%)

Netherlands(n=16)

8 (32%)

4 (31%)

7 (28%)

5 (31%)

0 (0%)

3 (19%)


Sirolimus-coated Stent for ISRSirolimus-coated Stent for ISR

First-In-Man Experience (n=38/41)

%DS

0

1

2

3

0.90.9

2.72.7 2.62.6MLD(mm)

0.70.70.7

2.62.62.6 2.52.52.5

74.6

1.6 5.7

62.2

2.6 7.6 Late LossBrazil = 0.08mmNetherl = 0.11mm

80%DS (Brazil)

60 %DS (Netherl)MLD (Brazil)40 MLD (Netherl)

20

0Pre Post 4mo

AHA 2002


Sirolimus-coated Stent for ISRSirolimus-coated Stent for ISR1-Year Clinical Events

0 (0%)

0 (0%)

0 (0%)

1 (4%)

BrazilN=25

2 (4.9%)

1 (2.4%)

2 (4.9%)

3 (7.3%)

2 (12.5%)

1 (6.3%)

2 (12.5%)

2 (12.5%)

Death

MI

TLR

Restenosis

PooledN=41

RotterdamN=16

AHA 2002


IVUS Volumetric Analysis at Proximal Reference

IVUS Volumetric Analysis at Proximal Reference

Vessel volumeVessel volume 72±44

72±44

-0.44

-0.44

PostPost FUFU DeltaDelta

Lumen volumeLumen volume 50±550±5 -1.81-1.81

Plaque volume

Plaque volume

34±23

34±23

0.080.08

Proximal

Proximal

72±46

72±46

52±60

52±60

34±22

34±22p=NSp=NSAll values in mm2All values in mm2

Edge effect was not seen in Edge effect was not seen in Cypher stentCypher stent !!


Late Lumen Loss in Drug-Eluting Stent vs. Radiation in ISR Trials

Late Lumen Loss in Drug-Eluting Stent vs. Radiation in ISR Trials

0.200.28

0.38

0.09

Sirolimus WRIST PREVENT START

Average Bare Stent Late Lumen Loss = 0.80

0.80

0.60

0.40 Angiographic Standard Deviation

of 0.1mm x 2

-0.60

-0.40

-0.20

0.00

Late

Los

s (m

m)

0.20

90Sr192I 32P6 mo4 mo 6 mo 8 mo

-0.80


Drug-Eluting Stent forIn-Stent Restenosis

We need more data.However, we suppose that it may be an alternative standard therapy to intracoronary brachytherapy.

Documents

PCI for Lesion with In-stent Restenosis restenosis.pdfPCI for Lesion with In-stent Restenosis. ... Therapy for In-Stent Restenosis: AMC Experience. Cardiovascular Research Foundation