Advanced Angioplasty 2008 London Sequent Paclitaxel-Elutng Balloon Scientific Program Wolfgang Bocksch,M.D.,PhD. Director Cardiac Catheterization Laboratories Charité-Campus Virchow Klinikum, Berlin, Germany

My Conflict of Interests Advisory board Boston 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: µg Paclitaxel / mm² (AcR[regular])  High dose: 4 – 5.5 µg Paclitaxel / mm² (AcH) Drug eluting balloon (DEB) Coating 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: vessel area [mm²]luminal area [mm²]neointimal area [mm²] control, n=12EEER, n=9AcL, n=10AcR, n=9 ns 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 study FIM (n=52) Scheller et al. NEJM 2006:335:

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 study Scheller et al. NEJM 2006:335:

Paccocath ISR I study QCA / primary endpoint: In-segment analysis ControlPaccocathp Lesion length18.2 ± 7.9 mm17.9 ± 6.1 mm0.868 Reference diameter3.03 ± 0.37 mm2.93 ± 0.47 mm0.463 Minimal lumen diameter initial0.69 ± 0.39 mm0.72 ± 0.35 mm0.811 Minimal lumen diameter post PTCA 2.52 ± 0.47 mm2.44 ± 0.55 mm0.603 Minimal lumen diameter 6 months 1.71 ± 0.91 mm2.30 ± 0.74 mm0.020 Late lumen loss (in segment)0.82 ± 0.86 mm0.13 ± 0.51 mm Binary restenosis rate40.9 %8.7 %0.017 Scheller et al. NEJM 2006:335:

Paccocath ISR I study MACE – 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 Balloon 2 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 P aclitaxel- E luting P TCA-Balloon Catheter in C oronary A rtery D isease 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 DEB 6 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 ± Follow-up: clinical 62 (93.9%) 59 (98.3%)0.4 Follow-up: angiographic54 (81.8%) 53 (83.3%) 0.5 Late lumen loss [mm] 0.19 ± ± Binary restenosis in segment2/54 (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%) protocol violators excluded 2 NSTEMI side branch occlusion 4 non-cardiac death 3 cardiac, 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 ?? ISRNative plaque Concentriceccentric Homogenousheterogenoeus No Lipidlipid-rich Extracellular matrixInflammation

PEPCAD I trial “The P aclitaxel- E luting P TCA-Balloon Catheter to Treat Small Vessel C oronary A rtery D isease”

PEPCAD I – Objective / Study Design Objective The objective of this study is to assess the safety and efficacy of the Paclitaxel-eluting PTCA-balloon catheter (3µg/mm 2 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 Design This 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 daily 1 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 failure 4/118 (3.4%) Conventional balloon 2/4(50%) Drugs 2/4 (50%) DEB only 82/114 (71.9%) DEB + BMS 32/114 (28.1%)

DEB Only (N=82)DEB & BMS (N=32) Follow-up clinical [months]6.7 ± ± 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 ± ± 0.67 Binary restenosis in segment4/73 (5.5%) 11/28 (39.3%) Binary restenosis in lesion4/73 (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 Objective The 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 Design This study is a prospective, randomized, multi- center, two-armed phase-II pilot study conducted in Europe.

PEPCAD I SeQuent Please for small vessels, 6-month-angiographic follow-up GERMAN MULTICENTER TRIAL PEPCAD II SeQuent Please for the treatment of in-stent restenosis randomized with TAXUS paclitaxel eluting stent, 6- month-angiographic follow-up GERMAN MULTICENTER TRIAL January, 2006 PEPCAD III Coroflex® DEBlue for complex lesions randomized with Cypher Select, 9-month-angiographic follow-up EUROPEAN MULTICENTER TRIAL PEPCAD IV SeQuent® Please with subsequent Coroflex® Blue implantation for diabetics randomized with Taxus, 9-month-angiographic follow-up ASIAN MULTICENTER TRIAL PEPCAD V Bifurcation pilot study, Coroflex® Blue in main vessel and SeQuent® Please for sidebranch, 9-month follow- up German MULTICENTER TRIAL PEPCAD VI CTO pilot study, SeQuent® Please for chronical total occlusions, 6-month follow-up German 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: Scheller, Z Kardiol 2005; 94: sustained drug release essential DES 28 days

Paclitaxel Coated Balloon Efficacy versus paclitaxel dose / mm² balloon surface 1,3 2,5 3,0 5,010, ,02,03,04,05,06,07,08,09,010,0 %inhibition of neointimal area μg paclitaxel / mm² balloon surface

DEB vs. Cypher™ Stent AcR Paclitaxel 3 AcR Paclitaxel 3 µg/mm², 28 days follow-up, n= vessel area [mm²]luminal area [mm²]neointimal area [mm²] controlDEBSES p=0.001* p=0.002* p-values * vs control ** DEB vs Cypher p=0.001* p=0.013* p=0.004** p=0.103** p=0.718* p=0.267* p=0.157**

Late loss in-segment - comparison Paccocath ISR I with ISAR DESIRE *data from ISAR DESIRE; Kastrati, JAMA 2005; 293: Paccocath ISR I study

PEPCAD I Outcome (ITT: N=120) Follow-up: clinical 117/120 (97.5%) Follow-up [months] 6.7 ± 2.1 Follow-up: angiographic 103/120 (85.8%) Follow-up [months] 6.3 ± 1.8 Late lumen loss [mm] 0.30 ± 0.55 Binary restenosis in segment 16/103 (15.5%) Binary restenosis in lesion 15/103 (14.6%) Total MACE 16/117 (13.7%) TLR 14/117 (12.0%) Myocardial infarction* 2/117 ( 1.7%) Death 0 *1 One NSTEMI due to occlusion of non-target vessel

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 %.