Advanced Angioplasty 2008Advanced Angioplasty 2008London 23.1.-25.1.2008London 23.1.-25.1.2008

Sequent Paclitaxel-Elutng Balloon Sequent Paclitaxel-Elutng Balloon Scientific ProgramScientific Program

Wolfgang Bocksch,M.D.,PhD.

Director Cardiac Catheterization Laboratories

Charité-Campus Virchow Klinikum, Berlin, Germany

My Conflict of Interests

Advisory boardBoston Scientific

B.Braun Vascular Systems

• Procedure EEE Ethyl acetate as solvent

2 µg Paclitaxel / mm² balloon surface (EEER)

• Procedure Ac Aceton as solvent + iopromide as additive

Low dose: 1.3 µg Paclitaxel / mm² (AcL)

Medium dose: 2.5 - 3 µg Paclitaxel / mm² (AcR[regular])

High dose: 4 – 5.5 µg Paclitaxel / mm² (AcH)

Drug eluting balloon (DEB)

Coating technologyCoating technology

• Coating of conventional angioplasty balloon catheters (Sequent)

• Controlled dose, homogeneity of coating, non-toxic agents

DEB- porcine restenosis study• coronary stent implantation LAD + CX with study balloon:• uncoated control, EEER, AcL, AcR; 28 days follow-up, n=40

Scheller et al. Circulation 2004;110:810 - 4

0

1

2

3

4

5

6

7

8

vessel area [mm²] luminal area [mm²] neointimal area [mm²]

control, n=12 EEER, n=9 AcL, n=10 AcR, n=9ns

p=0.001

p=0.001

• Comparison DEB vs. conventional PTCA catheter

• Safety and efficacy of paclitaxel coated balloon (Sequent-DEB) in

BMS-ISR

• Randomized, double-blind multicenter trial

• Coronary BMS-ISR (80% diffuse and 20 focal, < 30mm)

• Repeated PTCA of BMS-ISR vs. using the Sequent DEB

–3 µg paclitaxel / mm² balloon surface or a non-coated balloon of the same type (control group)

• 6-week-clopidogrel only

Paccocath ISR I studyPaccocath ISR I study

FIM (n=52)FIM (n=52)

Scheller et al. NEJM 2006:335:2113-24

• Main inclusion criteria

– Clinically relevant coronary BMS-ISR

– Diameter stenosis of at least 70 %

– < 30 mm length

– Vessel diameter of 2.5 to 3.5 mm

• Primary endpoint

–Late lumen loss after 6 months • independent, blinded Core lab

• Secondary endpoints

–Binary restenosis rate 6 m.

–MACE (TLR, myocardial infarction, death) 12 m.

Paccocath ISR I studyPaccocath ISR I study

Scheller et al. NEJM 2006:335:2113-24

Paccocath ISR I studyPaccocath ISR I studyQCA / primary endpoint: In-segment analysisQCA / primary endpoint: In-segment analysis

  Control Paccocath p

Lesion length 18.2 ± 7.9 mm 17.9 ± 6.1 mm 0.868

Reference diameter 3.03 ± 0.37 mm 2.93 ± 0.47 mm 0.463

Minimal lumen diameter initial 0.69 ± 0.39 mm 0.72 ± 0.35 mm 0.811

Minimal lumen diameter post PTCA

2.52 ± 0.47 mm 2.44 ± 0.55 mm 0.603

Minimal lumen diameter 6 months

1.71 ± 0.91 mm 2.30 ± 0.74 mm 0.020

Late lumen loss (in segment) 0.82 ± 0.86 mm 0.13 ± 0.51 mm 0.002

Binary restenosis rate 40.9 % 8.7 % 0.017

Scheller et al. NEJM 2006:335:2113-24

Paccocath ISR I studyPaccocath ISR I studyMACE – longest available follow-upMACE – longest available follow-up

TLR, MI, acute/subacute closure,

stroke, or death

November 1, 2006; Mantel-Cox log-rank test; p-values adjusted according to Fisher’s method of combining independent tests

Drug-eluting Balloon2 questions

•Is the Sequent-DEB equally effective or superior to DES for the treatment of BMS-ISR ??

•Is the DEB also effective in native coronary atheroma

PEPCAD II trial

“The Paclitaxel-Eluting PTCA-Balloon Catheter in

Coronary Artery Disease to Treat BMS-In-Stent Restenoses:

A Comparison to the Paclitaxel-Eluting Taxus™ Stent –

PEPCAD II – Objective / Study Design

•Objective The aim of the study is to assess the safety and efficacy of the Paclitaxel-eluting PTCA-balloon in the treatment of BMS-In-stent restenoses in native coronary arteries with reference diameters between  2.5 mm and  3.5 mm and ≤ 22 mm in length for procedural success and preservation of vessel patency in comparison to the Paclitaxel-eluting Taxus™ stent.

•Study Design This study is a prospective, randomized, multi-center, two-armed phase-II study.

Primary Endpoint

•6-month late lumen loss

Secondary Endpoint

•Procedural success (≤30%)

•6-month binary restenosis rate

•6-month MACE

•MACE at 1 and 3 years

PEPCAD II trial“The Paclitaxel-Eluting PTCA-Balloon Catheter in

Coronary Artery Disease to Treat BMS-In-Stent Restenoses: A Comparison to the Paclitaxel-Eluting Taxus™ Stent –

Inclusion Criteria

• Stable or unstable angina (no MI) • BMS-ISR in native coronary arteries

Medication

• ASS ≥ 100 mg daily• Clopidogrel 75 mg daily

3 months DEB6 months DES

PEPCAD II trial“The Paclitaxel-Eluting PTCA-Balloon Catheter in

Coronary Artery Disease to Treat BMS-In-Stent Restenoses: A Comparison to the Paclitaxel-Eluting Taxus™ Stent –

PEPCAD II trial DEB (N=66) DES (N=60) P=

Follow-up [months] 6.2 ± 0.8 6.2 ± 0.8 0.7

Follow-up: clinical 62 (93.9%) 59 (98.3%) 0.4

Follow-up: angiographic 54 (81.8%) 53 (83.3%) 0.5

Late lumen loss [mm] 0.19 ± 0.39 0.45 ± 0.69 0.01

Binary restenosis in segment 2/54 (3.7%) 11/53 (20.8%) 0.02

Total MACE 3/62 (4.8%) 13/59 (22.0%) 0.007

TLR 2/62 (3.2%) 11/59 (18.6%) 0.008

Myocardial infarction 0/62 (0.0%) 1/59 (1.7%) 2 1

Death 1/62 (1.6%)3 1/59 (1.6%) 4 1

1protocol violators excluded 2 NSTEMI side branch occlusion4 non-cardiac death3cardiac, not lesion related

PEPCAD II Summary

The paclitaxel-eluting balloon catheter Sequent Please …

– was safe and associated with a high procedural success rate in BMS-ISR, – exhibited low late lumen loss after 6 months in BMS-ISR, – was superior to the paclitaxel-eluting Taxus stent in BMS-ISR after 6 months,

and in TLR– has not been associated with late thrombosis in 200 patient years in BMS-ISR.

even though dual antiplatelet therapy was given only for 3 months

Is the DEB equally effective in native CAD ??

ISR Native plaqueConcentric eccentricHomogenous heterogenoeusNo Lipid lipid-richExtracellular matrix Inflammation

PEPCAD I trial

“The Paclitaxel-Eluting PTCA-Balloon Catheter to

Treat Small Vessel Coronary Artery Disease”

PEPCAD I – Objective / Study Design

•ObjectiveThe objective of this study is to assess the safety and efficacy of the Paclitaxel-eluting PTCA-balloon catheter (3µg/mm2 balloon surface area) in the treatment of significant (≥ 70% and < 100 %) stenoses in native coronary arteries with reference diameters from  2.25 mm to  2.8 mm and ≤ 22 mm in length for procedural success and preservation of vessel patency.

•Study DesignThis study is a prospective, non-randomized, multi-center, one-arm phase-II pilot study

Primary Endpoint •6-month late lumen loss

Secondary Endpoint•Procedural success

•6-month binary restenosis rate

•6-month MACE

•MACE at 1 and 3 years

PEPCAD I trial “The Paclitaxel-Eluting PTCA-Balloon Catheter

to Treat Small Vessel Coronary Artery Disease”

Inclusion Criteria

• Stable or unstable angina (no MI)

• De-novo lesion in native coronary arteries

Medication

• ASS ≥ 100 mg daily

• Clopidogrel 75 mg daily1 month DEB only

3 months DEB with additional non-DES stent

PEPCAD I trial “The Paclitaxel-Eluting PTCA-Balloon Catheter

to Treat Small Vessel Coronary Artery Disease”

PEPCAD I Patient Flow Chart

Enrolled 120 Subj.

DEB 114/118 (96.6%)

Violation 2/120 (1.7%)Muscle bridge

Lesion 50%, no PCI

Crossing failure4/118 (3.4%)

Conventional balloon 2/4(50%)Drugs 2/4 (50%)

DEB only82/114 (71.9%)

DEB + BMS32/114 (28.1%)

DEB Only (N=82) DEB & BMS (N=32)

Follow-up clinical [months] 6.7 ± 1.9 6.2 ± 1.3

Follow-up: clinical [N] 82 (100%) 30 (93.75%)

Follow-up: angiographic 73 ( 89%) 28 (87.5%)

Late lumen loss [mm] 0.18 ± 0.38 0.67 ± 0.67

Binary restenosis in segment 4/73 (5.5%) 11/28 (39.3%)

Binary restenosis in lesion 4/73 (5.5%) 10/28 (35.7%)

TLR 4/82 (4.9%) 9/30 (30.0%)

Myocardial infarction 1/82 (1.2%) *1/30 (3.3%)

Death 0/82 (0 %) 0/30 (0 %)

*NSTEMI due to occlusion of non-target vessel

Total MACE 5/82 (6.1%) 10/30 (33.3%)

PEPCAD I Outcome

PEPCAD III trial

“Paclitaxel-Eluting PTCA-Balloon in Combination with the Coroflex Blue Stent vs

the Sirolimus Coated Cypher Stent in the Treatment of Advanced Coronary Artery Disease”

The patient recruitment of 600 patients started in July 2007.

PEPCAD III – Objective / Study Design

• ObjectiveThe aim of the study is to assess the safety and efficacy of the Paclitaxel-eluting Coroflex DEBlue stent system in the treatment of stenoses in native coronary arteries with nominal stent diameters between ≥ 2.5 mm and ≤ 3.5 mm and < 24 mm in length for procedural success and preservation of vessel patency in comparison to the Sirolimus-eluting Cypher stent.

• Study DesignThis study is a prospective, randomized, multi-center, two-armed phase-II pilot study conducted in Europe.

PEPCAD ISeQuent Please for small vessels, 6-month-angiographic follow-upGERMAN MULTICENTER TRIAL

PEPCAD IISeQuent Please for the treatment of in-stent restenosis randomized with TAXUS paclitaxel eluting stent, 6-month-angiographic follow-upGERMAN MULTICENTER TRIAL

January, 2006

PEPCAD IIICoroflex® DEBlue for complex lesions randomized with Cypher Select,9-month-angiographic follow-upEUROPEAN MULTICENTER TRIAL

PEPCAD IVSeQuent® Please with subsequent Coroflex® Blue implantation for diabetics randomized with Taxus,9-month-angiographic follow-upASIAN MULTICENTER TRIAL

PEPCAD VBifurcation pilot study, Coroflex® Blue in main vessel and SeQuent® Please for sidebranch, 9-month follow-up German MULTICENTER TRIAL

PEPCAD VICTO pilot study, SeQuent® Please for chronical total occlusions, 6-month follow-upGerman MULTICENTER TRIAL

Drug-eluting balloon clinical program (B.Braun)

DEB Sequent Please Summary

The paclitaxel-eluting balloon catheter Sequent Please …

–is so far the most potent and easiest device to treat focal/diffuse BMS-ISR,

–avoids 6-12 month clopidogrel/Ticlopidine therapy –is a promising device for the treatment of native atheroma especially in small vessels

–The role of DEB in complex disease as bifurcations, CTOs, SVGs has to be determined in further studies

Drug-Eluting Stents

Hwang, Circulation 2001; 104: 600-5

Scheller, Z Kardiol 2005; 94: 445-452

sustained drug release essential

DES 28 days

PEPCAD I Summary

The paclitaxel-eluting balloon catheter Sequent Please …

–was safe and associated with a high procedural success rate in de-novo lesions in small vessels,

–exhibited low late lumen loss after 6 months , and–patients treated per protocol (w/o additional stenting) demonstrated a restenosis rate of 5.5 %.