DCB研究进展 郭 伟，熊 江 pla301dml@vip.sina.com 解放军总医院血管外科 全军血管外科中心 郭 伟，熊 江 pla301dml@vip.sina.com 解放军总医院血管外科 全军血管外科中心 北京市重点学科 北京市重点实验室

Fem-pop Artery – Biomechanics Bend / Kink Zone A Zone B Zone C Fixed Compress / Slight curve Zone D * Lansky, A; Angiographic Analysis of Strut Fractures in the SIROCCO Trial. TCT 2004 2

Fem-pop Artery – Biomechanics * Alexander Nikanorov, et al. Fracture of self-expanding nitinol stents stressed in vitro under simulated intravascular conditions. J vascular surgery 2008;48(2):435-440

Fem-pop Artery – Biomechanics 轴向压缩比例 （无支架） 轴向压缩比例 （100mm支架） * Alexander Nikanorov, et al. Fracture of self-expanding nitinol stents stressed in vitro under simulated intravascular conditions. J vascular surgery 2008;48(2):435-440

Diffuse in-stent restenosis Fracture and Restenosis Fracture Diffuse in-stent restenosis

Fracture and Restenosis 扭结风险

Clinical Trials Everflex （DURABILITY II） Lifestent （RESILIENT） Zilver （ZILVER PTX） Luminexx （FAST） Smart Long （SMART） Complete SE （COMPLETE）

Drug Coating Balloon （DCB） PTX 紫杉醇

DCB History 1st Generation: 2001 Paccocath; Paclitaxel eluting balloon «hand-made» prototypes from University in Germany. 1st Formulation was developed to inject into artery, not intended to be a coating formulation for balloons 10

1st Generation DEB The following products are based on the first Generation technology Approval: 2011 A Bayer-Schering Company CE-approved, no significant sales Technology for sales Approval: 2009 Coronary only, NO peripheral DEB Old technology 11

2nd Generation DEB Paclitaxel-Eluting Formulation optimized. Complex ioprmide additive of first generation replaced by better additive for balloons. Ioprmide 碘普罗胺 Additive 添加剂 12

2nd Generation DEB The following products are based on the 2nd Generation technology Approval: 2010 Market leader in DEB PTA Approval: 2011 Bard Acquired Approval: 2011 Peripheral DEB, 0.018 System only Approval Dior II: 2009 Focus on Coronary only (Freeway PTA is based on PTCA) Approval Coronary: 2010 Peripheral product launch planned 2013 13

3rd Generation DEB 3rd Generation Optimization of whole system Paclitaxe-eluting formulation optimized for Angioplasty Balloon Catherters and balloon catheter optimized for drug elution in peripheral vessels. Acotec seems to be the first company with a 3rd Generation DEB, optimizing the whole system for PTA 14

Paclitaxel Paclitaxel is used to reduce restenosis in arterial indications since more than 10 years. The drug substance on the balloon is in dry state. Paclitaxel is intravenously infused up to a dose of 175mg/m2 body surface equivalent to ca. 300 mg/ patient. Usually, the treatment is repeated several times with a treatment-free interval of 1 month 3 µg Paclitaxel /mm2 Balloon surface results for the largest balloon (Ø 7 x 300 mm) in about 20 mg There is a high safety marging

Why Paclitaxel? Drug concentration in Tissue (TBC) Sirolimus 西罗莫司 * A. Levin et al., Proc Natl Acad Sci USA, 2004, 101, 9463-9467

Why Paclitaxel? DEB DES 17

Additive Magnesium stearate is a well known pharmaceutical excipient. The components ‘magnesium ions and stearic acid are essential components of blood and tissues. Magnesium stearate  content of a large balloon catheter (Ø7x300 mm) is less than 0.5 mg whereas plasma contains about 20-30 mg magnesium/ 1 liter. Stearate is a major component of lipids, cell membranes etc; the total amount in the body is several gram. The additive and its amount is considered harmless

Dose Animal Study Porcine Coronary Arteries 28 Days FU 46 Animals Treated

Dose Study Investigative Radiology • Volume 46, Number 4, April 2011 www.investigativeradiology.com 20

Dose Study * Kelsch et al; Investigative Radiology; April 2011 21

High safety and efficacy margin Dose Study Significant reduction of all parameters Characterizing stenosis was seen in the groups of 1 µg to 9 µg (3 times the dose) 3 µg seems the most efficacious dose No adverse events up to 3 times standard dose 9 times standard dose showed 3 occlusion Reason for occlusion stays unclear, but can also be due to multiple balloon inflations at the same location resulting in vessel injury High safety and efficacy margin

Pharmacokinetics Animal Study Porcine Coronary Arteries up to 6 months FU 30 Animals Treated

Pharmacokinetics Study 24

Pharmacokinetics Study * Speck et al; Circ CV Int; 2012;5 25

Pharmacokinetics Study Paclitaxel stays in the vessel wall of pigs long enough to explain persistent inhibition of neointimal proliferation At 1 month the Paclitaxel content was about 2.5 % of the original dose At 6 months the Paclitaxel content was below 0.5% of

Inflation time Animal Study Porcine Coronary Arteries 28 Days FU 28 Animals Treated

Inflation time Study Tromb Haemost 2009 ; 101 : 201-206 28

Inflation time Study * Cremers et al; DEB: Very short term exposure and overlapping; Thromb Haemost 2009 29

Inflation time Study 30 s - 60 s inflation time is recommended Longer inflation time did not change the results Nominal pressure is enough to apply the drug * Cremers et al; DEB: Very short term exposure and overlapping; Thromb Haemost 2009 30

DEB PTA Clinical Study Thunder Study Gunar Tepe, Germany Randomized Multicenter Study, 154 Patients PTA vs DEB

* N ENGL J MED 35;7 WWW.NEJM.ORG FEBRUARY 14, 2008

Late Lumen Loss (LLL) * Tepe et al; Local delivery of paclitaxel to inhibit restenosis during PTA; NEJM 358:7; 2008

Target Lesion Revascularization(TLR) * Tepe et al; Local delivery of paclitaxel to inhibit restenosis during PTA; NEJM 358:7; 2008

DEB PTA Clinical Study FemPac Study Michael Werk, Germany Randomized Multicenter Study, 87 Patients PTA vs DEB

(Circulation. 2008; 118: 1358-1365. ) 36

Late Lumen Loss (LLL) * Werk et al; Inhibition of Restenosis in Femoropopliteal Arteries; Circulation 2008

Target Lesion Revascularization (TLR) * Werk et al; Inhibition of Restenosis in Femoropopliteal Arteries; Circulation 2008

DEB PTA Clinical Study Pacifier Study Michael Werk, Germany Randomized Multicenter Study, 91 Patients PTA vs DEB

40

Late Lumen Loss (LLL) * Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5

Target Lesion Revascularization (TLR) * Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5 42

Late Lumen Loss (LLL) * Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5 43

DEB PTA: Current Companies Approved in Europe and CE related contries China: Certification process started Approved in Europe and CE related contries China: --- Coronary only, NO peripheral DEB China: --- Approved in Europe, focus on US China: --- Approved in Europe and CE related contries China: --- Approved in Europe focus on Coronary China:--- Approved in Europe, Launch 2013 China: --- Development finalized, CE registration process started China: Certification process started

国内DCB多中心临床研究 中国人民解放军总医院 郭 伟 复旦大学附属中山医院 符伟国 中山大学附属第一医院 王深明 郭 伟 复旦大学附属中山医院 符伟国 中山大学附属第一医院 王深明 上海交通大学医学院附属仁济医院 张纪蔚 辽宁省人民医院 吴丹明 首都医科大学附属北京世纪坛医院 张福先 中国中医科学院西苑医院 庄百溪 山东省立医院 金 星 河北医科大学第二医院 毕 伟 大连医科大学附属第一医院 王 峰 重庆医科大学附属第一医院 赵 渝 福建医科大学附属第一医院 郭平凡 45

试验设计 前瞻性、多中心、随机对照的临床验证研究 预计病例总数200例，试验组和对照组各100例 采用中央注册登记管理，通过登陆网站（IWRS）对受试者进行随机登记，计算机系统将根据受试者情况自动分配随机号，保证患者入组的公正性 计划入组时间6个月，随访12个月 46

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