1. DCB: What Is The Evidence? 药涂球囊临床研究进展
复旦大学附属
中山医院血管外科
郭大乔

2. 202 Million people in the world have PAD
The estimated number of people living with PAD increased 23.5% between 2000 and 2010
The estimated number of people in high-income countries with PAD increased 13.1% between 2000 and 2010
2000年至2010年预计外周动脉疾病的患者增长了百分之23.5
2000年至2010年高收入国家预计外周动脉疾病的患者增长了百分之13.1
20 Million
15 Million
10 Million
5 Million
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Fowkes et al. Lancet epub Aug 1, 2013 doi: /S (13)
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3. Endoarterial Continuum of Care 动脉血管内治疗的连续性
MEDICAL
THERAPY
药物治疗
PTA
血管成形术
STENTS
支架植入
BYPASS 搭桥
AMPUTATION 截肢
HEALTHY LEG
ATHERECTOMY
斑块旋切
Less Invasive更少创伤性
Decreasing Options/Irreversibility
More Invasive更具创伤性
So how do we treat PAD once it’s diagnosed?
This slide depicts Covidien’s treatment philosophy, which we refer to as the PAD Continuum of Care. It shows the progression of treatment options from least invasive on the left – beginning with a healthy leg and screening, -- and ends on the right with the most invasive treatment – loss of leg through amputation.
Ultimately, the goal is to save the patient’s life, but the importance of preserving quality of life by saving the leg cannot be underestimated. The farther one moves to the right on the treatment continuum, the more irreversible the treatment becomes, limiting long-term treatment options.
While PAD can be treated, it cannot be cured. As such, patients entering the hospital system for PAD will likely require reintervention after each stage of treatment, as well as additional management of the co-morbidities linked to PAD. As such, we believe that using the least invasive treatment options as the first line of treatment will help preserve the native vessel, thereby keeping more treatment options open for PAD patients.
那么一旦确诊外周动脉疾病我们该如何治疗？
这张幻灯片描述了Covidien的治疗理念，我们称之为外周动脉疾病连续性治疗。它示出了治疗方案从左侧的较少的创伤性治疗进展 - 开始一个健康的腿和筛选， - 并且结束在右侧最具创伤性治疗 - 腿的截肢。
最终的目标是挽救病人的生命，但保肢及生活质量的重要性不能被低估。越是移动到右侧治疗步骤，越是不可逆的治疗，并且远期效果更差。
而PAD是可以治疗的，但不能治愈。因此，进入医院系统为PAD患者都将可能需要再次介入治疗，以及与PAD相关的医疗管理。因此，我们认为，用最少的微创治疗方法为治疗的第一线将有助于维护患者的自身血管，从而是的PAD患者始终有更多的治疗选择
Where do NEW procedures & devices fit?
新的程序和器械适合哪儿？
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4. An Effective DCB Catheter Formulation Should… 理想的药涂球囊的要求
Use the lowest possible dose needed to achieve therapeutic tissue levels以最小剂量达到治疗所需要的组织浓度
Retain drug on the balloon during transit to the lesion
保证球囊通过病变时涂层药物保持不变
Ensure rapid drug transfer upon balloon inflation
保证球囊膨胀时药物能快速转移
Produce a uniform, durable, transfer efficient coating
生产出一致的、耐用的、有效转移的涂层药物
Demonstrate histologic “Drug-Effect” at least 28 days post treatment by light microscopy in preclinical models as the experience from DES is extensive
组织学证明“药物效应”治疗后至少28天在光镜下的临床前模型，在载药支架上有大量经验的

5. Drug-load balloon with 2 of paclitaxel 药涂球囊涂以2μg/mm2的紫杉醇
IV approved carriers of
polysorbate & sorbitol
载体为聚山梨醇酯和山梨醇
Uniform coating
统一规格的药物涂层
Manufacturer: Lutonix, Inc., a subsidiary of C. R. Bard

6. For Lutonix, Inc. a Subsidiary of C. R. Bard Presentation Use Only
Lutonix® Optimized Coating Formulation Showed Favorable Downstream Safety in a Porcine Model 猪模型中Lutonix 的最优化涂层药物组合表现出理想的安全性
Downstream Safety Demonstrated at 1X and 4X Doses No infarcts or embolic-occlusive events observed
No particulate observed
No skeletal muscle necrosis observed
At 1x and 4x Doses:1倍及4倍药物剂量
No physiologically significant changes observed at 1x and 4x doses at 28, 90, and 180 Days.1倍及4倍剂量在28、90及180天没有生理学上重大改变
Very rare focal changes observed in small arterioles小动脉只有极少的病灶样改变
No embolic-occlusive events or particulate observed没有发现栓塞或微粒
No skeletal muscle necrosis observed没有发现骨骼肌坏死
For Lutonix, Inc. a Subsidiary of C. R. Bard Presentation Use Only

7. LUTONIX® DCB Catheter Technology LUTONIX载药球囊技术
Uniform 均一性
Durable 耐用性
Coating applied while balloon is inflated
当球囊膨胀式应用涂层
<0.1% drug loss after dry inflate test*
膨胀实验后<0.1%的药物损失
<0.1% drug loss after sheath insertion
置入鞘管后<0.1%的药物损失
Coating Uniformity Analysis*
Segment-to-Segment Variability
< 4%
Coating Variability:
± 1.3 µg
*Consistent variance across all Lutonix® balloons
Data on file at Lutonix

8. Also true at 1 hour in vivo
Ex Vivo Administration of Fluorescent-Labeled PTX to Excised Porcine Artery 猪的动脉离体切片荧光染色
10% Oregon green labeled paclitaxel incorporated into Lutonix DCB coating

9. Lutonix Drug Coated Balloon Catheter Mechanism of Action Lutonix药涂球囊作用机制
second minimum inflation transfers drug to endoluminal surface delivering a therapeutic dose最快30秒球囊扩张 将药物释放到血管腔表面达到治疗剂 量
2. PTX diffuses into the arterial wall from an endoluminal reservoir
紫杉醇从动脉壁扩散至血管腔内
3. Over time, therapeutic drug levels are sustained in deep cell layers after endothelial drug levels become sub- therapeutic 同时，治疗药物在深细胞 层达到治疗浓度后内皮层药物浓度变 成亚治疗浓度
4. Drug continues to inhibit restenosis in arterial wall while allowing the lumen to restore and re-endothelialize 药物能持续阻止 血管壁的内膜增生

10. SFA INTERVENTIONS 股浅动脉的介入治疗

11. Bard Peripheral Clinical Trial Program 巴德的外周临床试验项目
Bard/Lutonix is investing in rigorous clinical studies in PAD to expand and refine treatment options and indications. CLI patients face poor clinical outcomes with existing treatments and DCB is a viable option.
Lutonix DCB provides an innovative, state of the art solution for treating BTK/CLI patients that delivers an optimal amount of drug to the diseased vessel while minimizing systemic and downstream exposure.
Indication
Study
Design
# Pts
# Sites
Arms
Primary EP
PI(s)
SFA
LEVANT I
(FIH)
RCT
101
EU Multicenter
DCB vs. PTA
D. Scheinert
LEVANT 2
476
IDE
Global Multicenter
Safety & Efficacy
K. Rosenfield
Continued Access
Registry
650
DCB Alone
Rare Adverse Events
LEVANT Global
SFA Registry
~1000 EU
Multicenter
Event free survival NA
BTK
Lutonix BTK Clinical Trial
480
IDE Global Multicenter
P. Geraghty
J. Mustapha
M. Brodmann
Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use

12. LEVANT 2 Trial Summary LEVANT 2实验简介
Primary endpoints
Safety and primary patency of target lesion at 1 year
Number of patients/sites
476 Randomized (2:1) / 55 global sites
Follow-up
Clinical: 6, 12, 24 Months
Duplex Ultrasound (DUS): 0–30 days, 6,12, 24 months
Telephone: 1, 36, 48, 60 Months
National principal investigators
Ken Rosenfield: Mass General, Boston
Dierk Scheinert: Park Hospital, Leipzig, Germany
Status
First Patient Enrolled July 2011
Last Patient Enrolled July 2012
12 month follow-up visits now complete and monitored

13. LEVANT 2 Primary Endpoints LEVANT 2主要终点
Safety安全性
Efficacy 有效性
Composite of freedom from all-cause peri-operative death & freedom at 1 YEAR in the index limb from:1年内无围手术期死亡以及如下
Primary patency of the target lesion at 1 YEAR:1年的目标病变的通畅率
Amputation (above or below the ankle) 截肢
Absence of restenosis (defined by DUS PSVR ≥2.5 & freedom from target lesion revascularization (TLR)
没有再狭窄及再次干预
Re-intervention再次介入手术
Index-limb-related death与肢体有关的死亡

14. Major Inclusion Criteria 主要入组标准
Rutherford 2–4
Male or non-pregnant female ≥18 years old
Patient is willing to
Consent
Comply with follow up schedule
No in-stent restenosis
Length ≤15 cm
Diameter 4-6 mm
≥70% stenosis
CLINICAL CRITERIA临床标准
ANGIOGRAPHIC CRITERIA造影标准

15. Study Designed to Reduce Bias Against Control Group实验设计减少对控制组的偏倚
PTA Pre-Dilatation
With 1mm undersized Uncoated Balloon
Successful
Pre-Dilation
Suboptimal PTA:
Major flow limiting dissection
OR >70% residual stenosis
Randomize 2:1
Treat per standard practice
30 day follow-up for safety
Test Arm:
Dilatation with Drug Coated Balloon
Control Arm:
Dilatation with Uncoated Balloon
12 Month
Follow-up
12 Month
Follow-up

16. Bail-out Stenting Not Considered a TLR or Failure in LEVANT 2 在LEVANT 2中额外的支架植入并不认为是失败或是TLR
Unlike some pivotal stent studies for PMA
与PMA的一些关键支架的研究不同
Purpose: to assess and compare long-term performance of the treatment modalities alone
目的：评估和比较治疗方式的长期表现
More rigorous way to assess a device
更严格的方法来评估设备

17. Bail-out Stent considered a failure (Bail-out stents excluded)
Exclusion of Bail-out Stenting as TLR Makes a Difference去除额外的支架植入作为TLR将带来不同的数据结果
RESILIENT1
Zilver® PTX2 %
Bail-out Stent considered a failure
LifeStent®
PTA
Zilver® PTX
12-Month
Primary Patency (KM)
81.5
36.7
83.1
32.8
Stent vs. PTA only
(Bail-out stents excluded)
LifeStent®
ITT
PTA
(as treated)
Zilver® PTX
(optimal)
12-Month
Primary Patency (KM)
81.5
61.5
83.1
65.3
1 Circ Cardiovasc Interv 2010;3: & J Endovasc Ther 2012;19:1-9.
2 Circ Cardiovasc Interv 2011;4:

18. 6-month Data for Randomized Cohort6个月时随机群组的数据

19. Patients Enrolled 选取的病人
Patients Randomized (2:1)
N=476
Standard Practice
N=11
Roll-in
N=56

20. Baseline Demographics (ITT) 病人信息统计资料
DCB
Standard PTA
P-value
Pooled
Age, Mean ± SD (n)
67.8 ± 10.0 (316)
69.0 ± 9.0 (160)
0.207
68.2 ± 9.7 (476)
Male gender, % (n/N)
61.1% (193/316)
66.9% (107/160)
0.216
63.0% (300/476)
Obesity
34.8% (110/316)
30.6% (49/160)
0.360
33.4% (159/476)
Current Smoker
35.1% (111/316)
33.8% (54/160)
0.548
34.7% (165/476)
Dyslipidemia
89.6% (283/316)
85.6% (137/160)
0.208
88.2% (420/476)
Diabetes
43.4% (137/316)
41.9% (67/160)
0.758
42.9% (204/476)
Hypertension
89.2% (282/316)
87.5% (140/160)
0.572
88.7% (422/476)
CAD
49.7% (157/316)
48.1% (77/160)
0.748
49.2% (234/476)
Rutherford Grade
0.521
  2
29.4% (93/316)
34.4% (55/160)
31.1% (148/476)
  3
62.7% (198/316)
57.5% (92/160)
60.9% (290/476)
  4
7.9% (25/316)
8.1% (13/160)
8.0% (38/476)
ABI
0.7 ± 0.2 (306)
0.7 ± 0.2 (156)
0.364
0.7 ± 0.2 (462)

21. Lesion/Procedural Characteristics (ITT) 病变特点
DCB
Standard PTA
P-value
Pooled
Two lesions treated
1.9% (6/316)
3.1% (5/160)
0.400
2.3% (11/476)
Total Lesion Length (mm)
62.9 ± 41.5 (315)
63.6 ± 40.3 (160)
0.866
63.2 ± 41.1 (475)
Treated Length (mm)
107.7 ± 47.0 (316)
107.3 ± 49.3 (160)
0.933
107.6 ± 47.7 (476)
Calcification
59.2% (187/316)
57.5% (92/160)
0.726
58.6% (279/476)
  Severe
17.6% (33/187)
13.0% (12/92)
0.326
16.1% (45/279)
Total Occlusion
20.6% (65/316)
21.9% (35/160)
0.741
21.0% (100/476)
%DS post-treatment
23.4 ± 12.3 (316)
23.8 ± 12.3 (158)
0.703
23.5 ± 12.3 (474)
Bail-out Stenting
2.5% (8/316)
6.9% (11/160)
0.022
4.0% (19/476)
Dissection
63.7% (200/314)
72.3% (115/159)
0.060
66.6% (315/473)
Final Procedural Dissection Grade
0.075
    Grade A
59.5% (119/200)
53.9% (62/115)
57.5% (181/315)
    Grade B
36.5% (73/200)
35.7% (41/115)
36.2% (114/315)
    Grade C
4.0% (8/200)
10.4% (12/115)
6.3% (20/315)
Procedural success (core lab)
88.9% (281/316)
86.8% (138/159)
0.497
88.2% (419/475)
Geographic Miss (core lab)
7.9% (24/316)
<0.001
12.6% (60/476)

22. Composite Safety Endpoint - KM1 复合安全性终点
Freedom from Primary Safety Event
Survival
DCB
PTA
Days
%[95% CI]
30 days
99.4% [97.5, 99.8]
99.4% [95.6, 99.9]
183 days
94.0% [90.7, 96.2]
94.1% [88.9, 96.9]
Standard PTA
DCB
Log-Rank p-value = 0.962
Months
1Not pre-specified for hypothesis testing and not adjusted for multiplicity

23. Composite Safety Endpoint – 12 Mo 12个月的复合安全性终点

24. Primary Patency - KM1 通畅率
% Free from Primary Patency Event
Survival
DCB
PTA
Days
%[95% CI]
30 days
99.7% [97.8, 100.0]
100.0% [N/A]
183 days
92.3% [88.6, 94.8]
82.7% [75.6, 87.8]
Standard PTA
DCB
Log-Rank p-value = 0.003
Months
1Not pre-specified for hypothesis testing and not adjusted for multiplicity

25. Primary Patency – 12 Mo 12个月的通畅率

26. Freedom from TLR - KM1 目标病变未行血管重建的比例
% Free from TLR
Survival
DCB
PTA
Days
%[95% CI]
30 days
99.7% [97.8, 100.0]
100.0% [N/A]
183 days
96.0% [93.1, 97.7]
96.0% [91.3, 98.2]
Standard PTA
DCB
Log-Rank p-value = 0.964
Months
1Not pre-specified for hypothesis testing and not adjusted for multiplicity

27. Other Secondary Endpoints at 6 Months1 6个月时其他的次要终点
Measure
DCB % (n/N)
PTA % (n/N)
Difference2
P-value2
Binary Restenosis
17.4% (47/270)
33.8% (47/139)
-16.4%
<0.001
Composite Safety Endpoint Failure
8.0% (24/299)
8.6% (13/151)
-0.6%
0.016
(non-inferiority)
TVR
6.7% (20/298)
7.9% (12/151)
-1.2%
0.633
Death
0.7% (2/301)
1.3% (2/152)
-0.7%
0.497
Amputation
0.3% (1/299)
0.0% (0/151)
0.3%
0.366
Embolization (any during index procedure)
0.6% (2/316)
1.9% (3/160)
0.226
Re-intervention for Thrombosis or Embolism (target vessel)
0.3% (1/298)
0.7% (1/151)
-0.4%
0.623
1Proportions through close of 6-month follow-up window (212 days)
2Not pre-specified for hypothesis testing and not adjusted for multiplicity

28. Walking Impairment Questionnaire 步行损害问卷2
Change From Baseline1
DCB-PTA
Difference % (95% CI)
WIQ Total Score2
6.0% (0.1, 12.0)
Walking Distance Score
7.6% (0.1, 15.2)
Walking Speed Score
4.3% (-1.9, 10.5)
Stair Climbing Score
6.7% (-0.2, 13.5)
1Not pre-specified for hypothesis testing and confidence intervals not adjusted for multiplicity
2Combined score is calculated as the mean of the distance, speed, and stair scores.

29. Summary 汇总 Rigorous trial designed to reduce bias
严格的实验设计来减少偏倚
Controlled pre-dilatation prior to randomization to limit the number of bail-out stents控制的预扩张在随机分组之前，来限制额外的支架植入
Did not count bail-out stenting as TLR 额外的支架植入不计入TLR
Blinded clinician to DUS 临床医师对超声结果不可见
Six month data is promising regarding safety and efficacy6个月的安全性及有效性数据都十分可观