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
5 Million
10 Million
15 Million
20 Million
Fowkes et al. Lancet epub Aug 1, 2013 doi: 10.1016/S0140-6736(13)61249-0
202 Million people in the world have PAD
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Endoarterial Continuum of Care动脉血管内治疗的连续性
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MEDICAL
THERAPY
药物治疗
PTA血管成形术 STENTS
支架植入
BYPASS搭桥
AMPUTATION截肢
HEALTHYLEG
ATHERECTOMY
斑块旋切
Less Invasive 更少创伤性
Decreasing Options/Irreversibility
More Invasive 更具创伤性
Where do NEW procedures & devices fit?新的程序和器械适合哪儿?
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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 treatm
ent 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
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• 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
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
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
For Lutonix, Inc. a Subsidiary of C. R. Bard Presentation Use Only
LUTONIX® DCB Catheter TechnologyLUTONIX 载药球囊技术
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Durable 耐用性Uniform 均一性• 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
Data on file at Lutonix
Coating Uniformity Analysis*Segment-to-Segment Variability
< 4%
Coating Variability: ± 1.3 µg *Consistent variance across all Lutonix® balloons
Ex Vivo Administration of Fluorescent-Labeled PTX to Excised Porcine Artery
猪的动脉离体切片荧光染色
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10% Oregon green labeled paclitaxel incorporated into Lutonix DCB coating
Lutonix Drug Coated Balloon Catheter Mechanism of Action
Lutonix 药涂球囊作用机制
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1. 30 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
SFA INTERVENTIONS股浅动脉的介入治疗
Bard Peripheral Clinical Trial Program 巴德的外周临床试验项目
Indication Study Design # Pts # Sites Arms Primary EP PI(s)
SFA
LEVANT I(FIH) RCT 101 EU Multicenter DCB vs. P
TA LLL@6M D. Scheinert
LEVANT 2 RCT 476IDE
Global Multicenter
DCB vs. PTA Safety & Efficacy D. Scheinert
K. Rosenfield
LEVANT 2Continued Acce
ssRegistry 650
IDE Global Multicent
er
DCB Alone
Rare Adverse Events
D. ScheinertK. Rosenfield
LEVANT Global SFA Registry Registry ~1000 EU
MulticenterDCB Alon
eEvent free surviv
al NA
BTK Lutonix BTK Clinical Trial RCT 480 IDE Global Multi
centerDCB vs.
PTA
Safety & Efficacy
P. Geraghty J. Mustapha
M. Brodmann
Caution – Investigational Device, Limited by Federal (USA) Law to Investigational Use
LEVANT 2 Trial SummaryLEVANT 2 实验简介
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Primary endpoints Safety and primary patency of target lesion at 1 year
Number of patients/sites 476 Randomized (2:1) / 55 global sites
Follow-upClinical: 6, 12, 24 MonthsDuplex Ultrasound (DUS): 0–30 days, 6,12, 24 monthsTelephone: 1, 36, 48, 60 Months
National principal investigators
Ken Rosenfield: Mass General, BostonDierk Scheinert: Park Hospital, Leipzig, Germany
Status
First Patient Enrolled July 2011Last Patient Enrolled July 201212 month follow-up visits now complete and monitored
LEVANT 2 Primary EndpointsLEVANT 2 主要终点
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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
Major Inclusion Criteria主要入组标准
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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
12 Month Follow-up
PTA Pre-DilatationWith 1mm undersized Uncoated Balloon
Randomize 2:1
Test Arm:Dilatation with Drug Coated
Balloon
Control Arm:Dilatation with Uncoated
Balloon
Suboptimal PTA:Major flow limiting dissection
OR >70% residual stenosis
Treat per standard practice
30 day follow-up for safety
Study Designed to Reduce Bias Against Control Group 实验设计减少对控制组的偏倚
12 Month Follow-up
Successful Pre-Dilation
6-month Data for Randomized Cohort6 个月时随机群组的数据
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Patients Enrolled 选取的病人
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Patients Enrolled
N=543
Patients Randomized (2:1)
N=476
Roll-inN=56
Standard Practice
N=11
Baseline Demographics (ITT)病人信息统计资料
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DCB Standard PTA P-value PooledAge, 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)
Lesion/Procedural Characteristics (ITT)病变特点
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DCB Standard PTA P-value PooledTwo 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) 21.9% (35/160) <0.001 12.6% (60/476)
Composite Safety Endpoint - KM1
复合安全性终点
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Log-Rank p-value = 0.962Standard PTADCB
Months
Survival DCB PTADays %[95% CI] %[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]
Freedom from
Primary Safety Event
1Not pre-specified for hypothesis testing and not adjusted for multiplicity
Composite Safety Endpoint – 12 Mo 12 个月的复合安全性终点
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Primary Patency - KM1
通畅率
Months
% Free from
Primary Patency
Event Survival DCB PTADays %[95% CI] %[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 PTADCBLog-Rank p-value = 0.003
1Not pre-specified for hypothesis testing and not adjusted for multiplicity
Primary Patency – 12 Mo 12 个月的通畅率
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Freedom from TLR - KM1
目标病变未行血管重建的比例
% Free from TLR
Standard PTADCB
Log-Rank p-value = 0.964
Survival DCB PTADays %[95% CI] %[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]
Months 1Not pre-specified for hypothesis testing and not adjusted for multiplicity
Other Secondary Endpoints at 6 Months1 6
个月时其他的次要终点
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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) -1.2% 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
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 a
nd efficacy6 个月的安全性及有效性数据都十分可观
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