dcb 研究进展 郭 伟，熊 江 [email protected] 解放军总医院血管外科...
TRANSCRIPT
Fem-pop Artery – Biomechanics
* Lansky, A; Angiographic Analysis of Strut Fractures in the SIROCCO Trial. TCT 2004
Bend / Kink
Zone A
Zone B
Zone C
Bend / Kink
Fixed
Compress / Slight curve
2
Zone D
* 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 3
Fem-pop Artery – Biomechanics
轴向压缩比例
（ 100mm 支架）
4
* 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）
5
Fracture and Restenosis
Fracture
Diffuse in-stent restenosis
6
扭结风险
Fracture and Restenosis
Clinical Trials
• Everflex （ DURABILITY II ）
• Lifestent （ RESILIENT ）
• Zilver （ ZILVER PTX ）
• Luminexx （ FAST ）
• Smart Long （ SMART ）
• Complete SE （ COMPLETE ）
7
8
Drug Coating Balloon （ DCB ）
9
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
10
1st Generation DEB
The following products are based on the first Generation technology
11
11
• Approval: 2011• A Bayer-Schering Company• CE-approved, no significant sales• Technology for sales
• Approval: 2009• Coronary only, NO peripheral DEB• Old technology
12
• Paclitaxel-Eluting Formulation optimized.
• Complex ioprmide additive of first generation replaced
by better additive for balloons.
2nd Generation DEB
12
• Approval: 2011• Bard Acquired
2nd Generation DEB
13
The following products are based on the 2nd Generation technology
• Approval: 2010• Market leader in DEB PTA
• 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
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
14
• 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
Paclitaxel
15
Drug concentration in Tissue (TBC)
Why Paclitaxel?
16* A. Levin et al., Proc Natl Acad Sci USA, 2004, 101, 9463-9467
17
DEBDES
17
Why Paclitaxel?
• 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
Additive
18
Dose Animal Study• Porcine Coronary Arteries • 28 Days FU• 46 Animals Treated
19
20
20
Investigative Radiology • Volume 46, Number 4, April 2011 www.investigativeradiology.com
Dose Study
Dose Study
* Kelsch et al; Investigative Radiology; April 201121
• 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
Dose Study
22
PharmacokineticsAnimal Study• Porcine Coronary Arteries • up to 6 months FU• 30 Animals Treated
23
24
24
Pharmacokinetics Study
Pharmacokinetics Study
* Speck et al; Circ CV Int; 2012;525
• 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
the original dose
26
Pharmacokinetics Study
Inflation time Animal Study• Porcine Coronary Arteries • 28 Days FU• 28 Animals Treated
27
28
28
Inflation time Study
Tromb Haemost 2009 ; 101 : 201-206
Inflation time Study
* Cremers et al; DEB: Very short term exposure and overlapping; Thromb Haemost 200929
30
Inflation time Study
* Cremers et al; DEB: Very short term exposure and overlapping; Thromb Haemost 2009
• 30 s - 60 s inflation time is recommended• Longer inflation time did not change the results• Nominal pressure is enough to apply the drug
DEB PTA Clinical Study• Thunder Study• Gunar Tepe, Germany• Randomized Multicenter Study, 154 Patients• PTA vs DEB
31
Late Lumen Loss (LLL)
* Tepe et al; Local delivery of paclitaxel to inhibit restenosis during PTA; NEJM 358:7; 200833
Target Lesion Revascularization(TLR)
34* 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
35
36
36
(Circulation. 2008; 118: 1358-1365. )
Late Lumen Loss (LLL)
* Werk et al; Inhibition of Restenosis in Femoropopliteal Arteries; Circulation 2008
37
Target Lesion Revascularization (TLR)
38
* 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
39
40
40
Late Lumen Loss (LLL)
* Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5
41
42
42
Target Lesion Revascularization (TLR)
* Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5
43
43
* Michael Werk et al; Paclitaxel-Coated Balloons Reduce Restenosis after Femoro-Popliteal Angioplasty; Circ. Cardiovasc Interv. 2012;5
Late Lumen Loss (LLL)
DEB PTA: Current Companies
44
• 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
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
46
Thank you for your attention ！
47