1. 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
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

2. 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

3. 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):

4. 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):

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

6. Fracture and Restenosis
扭结风险

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

9. Drug Coating Balloon （DCB）
PTX 紫杉醇

10. 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

11. 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

12. 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

13. 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, 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

14. 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

15. 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

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

17. Why Paclitaxel?
DEB
DES 17

18. 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 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

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

20. Dose Study
Investigative Radiology • Volume 46, Number 4, April 20

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

22. 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

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

24. Pharmacokinetics Study24

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

26. 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

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

28. Inflation time Study
Tromb Haemost 2009 ; 101 : 28

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

30. 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

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

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

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

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

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

36. (Circulation. 2008; 118: ) 36

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

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

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

40. 40

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

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

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

44. 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

45. 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

46. 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

47. Thank you for your attention！