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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