The Evidence for Drug Coated Balloons Below The Knee:

SITE 2013

Dr Sumaira Macdonald MBChB (Comm.), FRCP, FRCR, PhD, EBIR Consultant Vascular Radiologist & Honorary Clinical Senior Lecturer,

Freeman Hospital, Newcastle, UK

Disclosures: Research / Educational Grants & / or consultancy:

Abbott Vascular

CR Bard

Ev3/Covidien

Pyramed

WL Gore Medtronic / Invatec

Biotronik

Cordis (J & J)

St Jude/AGA

Spectranetics

Tryton Medical

Silk Road Medical

Terumo

Merit Medical

Volcano

COOK

Vascular Perspectives

Bridgepoint / EPS vascular

Lecture Plan:

•  Natural history of CLI

•  Cost implications (amputation/ulcer)

•  Relationship of patency to limb salvage

•  Tissue healing paradigms & time-frame

•  The evidence base (registry data)

•  The evidence base (trial data)

The Natural History of CLI, & Cost Considerations:

N=136

Lepäntalo et al: EJVES 1996;11 (2): 153-157

54% mortality & 46% amputation rate in unreconstructed CLI at 1 year

Natural History of Critical Limb Ischaemia

QoL & Cost of Amputation

Rogers L et al. Journal of the American Podiatric Medical Association 2008;98:166-186

Estimated 2007 costs Potential Annual Cost Savings (billions)

The Relationship Between Patency & Limb Salvage:

Kudo T et al. JVS 2005;41:423-435

Outcomes after PTA in CLI (all vessel segments):

N = 111

Tissue healing paradigms

Is long term patency needed for ulcer healing ?

Optimal vascularisation

Vascularisation

Metabolic need

Trauma

Revascularisation

Patent

Restenosis

Time needed for healing Vermassen F 2010

Is long term patency needed for ulcer healing ?

Restenosis

Optimal vascularisation

Vascularisation

Metabolic need

Trauma

Revascularisation

Patent

Time needed for healing

New trauma

Vermassen F 2010

•  Sub-optimal perfusion renders tissues vulnerable

•  Durable perfusion is an insurance policy against ulcer recurrency and recrudescence

Optimal Vs. Suboptimal Perfusion:

Wound Healing Time:

2. Soderstrom JVS 2009 1. Xcell Trial Rocha Singh 2011

3. Soderstrom EJVES 2008 4. Hoffman EJVES 2007* 5. Chung JVS 2006

Average Time To Healing=6-12 Months (endo/hybrid)

*Complete ulcer healing=60-80%

The Evidence-Base For DCB BTK: Registry Data:

Fist Experience With Drug-Eluting Balloons In Infrapopliteal

Arteries: Restenosis Rate & Clinical Outcomes (Leipzig Registry)

Schmidt A et al. JACC 2011;58:1105-1109

Clinical Review at 12.5 Months

Schmidt A et al. JACC 2011;58:1105-1109

Single Unit Data: DCB Against Historical Controls

N = 77* N = 104**

Schmidt A et al. JACC 2011;58:1105-1109**

Schmidt A et al. Cath Cardiovasc Intervent 2010;76:1047-1054*

DEB (angio

subgroup)

PTA* (historical group)

3m Angiographic FU Restenosis (>50%) 27.4% 69%

Full-segment Resten. 10% 56% Restenosis Length 64 mm 155 mm

12m Clinical FU 15m Clinical FU

Deaths 16.3% 10.5% Limb Salvage 95.6% 100%

Clinical Improvement (1) 91.2% 76.5% Compl. wound healing 74.2% 78.6%

TLR 17.3% 50%

Restenosis Type:

Risk-Factors For Restenosis After DCB PTA:

The Evidence-Base For DCB BTK: Randomized Trials:

DEBATE- BTK Randomized Trial

Liistro F et al TCT 2011/LINC 2012

Medtronic InPact Amphirion

Angiographic & Procedural Characteristics

Clinical & Angiographic Outcome:

*

* Randomisation after lesion crossing

*

12-Month Binary Restenosis & Reocclusion:

Fanelli F et al JEVT 2012;19:571-580

Study design

Lesion Characteristics:

6-Month Late Lumen Loss:

0.5 +/- 1.4mm (DCB) Vs. 1.6 +/- 1.7mm (PTA)

P < 0.01

Secondary Endpoints (6 Months):

P < 0.001*

*Clinically and angiographically driven TLR

Clinical Outcomes:

* P < 0.05 compared to pre-procedure values

† P < 0.05 PTA Vs. DCB

“ Standard ” PTA in BTK: Restenosis & TLR Rates

D. Sheinert JACC 2012;60: 2290-2295

H.K Soder JVIR 2000;11: 1021-1031

F Bauman JVIR 2011;22:1665-1673

F Fanelli JEVT 2012;19: 571-580

F Liistro TCT 2012

A Schmidt Cathet Cardovasc Intervent 2012;76:1047-54

“ DCB ” PTA in BTK (InPact): Restenosis & TLR Rates

A Cioppa JEVT 2012;19:571-580 F Fanelli JEVT 2012;19: 571-580

F Liistro TCT 2012 K Suzuki LINC AP 2012 A Schmidt JACC 2011;58:1105-1109

Conclusions:

•  Failure to show amputation advantage over PTA

•  Underpowered for “ clinical endpoints ”

•  Lesion lengths representative (real world)

•  6/12 “ biologic ” data alone are not compelling

•  Early data (12 month patency & TLR) are promising: follow up/consolidation needed

Drug Coated Balloons:

•  6/12 “ biologic ” data alone are not compelling

•  Early data (12 month patency) promising: follow up/consolidation needed

•  Lesion lengths representative (real world)

•  Consistent “ class effect ” - paclitaxel

Conclusions:

Conclusions: Drug Eluting Stents:

•  Consistent class effect – the “ limus ” family

•  6 month – 12 month dual antiplatelet regime mandated

•  Lesion lengths unrepresentative (real world)

DCB & DES:

•  Failure to show amputation advantage over PTA

•  Underpowered for “ clinical endpoints ”

•  The cost-effectiveness argument will hinge on whether

vessel patency is relevant for this population

Conclusions: •  Early RCT & registry data increasingly support the use of DCB over PTA in CLI/BTK lesions

•  The cost-effectiveness argument will hinge on whether vessel patency is an advantage for this population

MedRad Cotavance: EURO CANAL & CANAL US

Euro CANAL Prospective multicentre EU Randomised Trial

20 Sites

120 patients with BTK lesions & CLI

1:1 RANDOMISTAION PTA. Vs. Cotavance DCB

CI Nicolas Diehm

CANAL US

CI William Gray & Gary Ansel

EuroCor:

Freeway 0.014” :

“ Full Drug Jacket ”

Prospective multicentre, non-randomised observational registry

CLI

CI Manzi M et al

N = 100

Enrolment start: Q1/2012

Enrolment finish: Q4/2013

*Lesion length 28 cm – two balloon overlap maximally

Current DCB paclitaxel dosing

DCBs Balloon Surface Dosing

Product

Paclitaxel (µg/mm2)

Dose on Balloon Surface

Lutonix 2 Paccocath® (Medrad)) 3

IN.PACT ™ (Invatec/Medtronic) 3

Dior® -Gen II (EuroCor) 3

n  PI: PD Dr. med. Nicolas Diehm – University Hospital Bern n  Prospective, multi-center, randomized trial conducted in

Europe n  25 patients enrolled as of April 2012 n  Co-Primary Efficacy endpoints:

l Angiographically-defined late lumen loss (LLL) of all randomized subjects at 6 months (independent core laboratory).

l Major amputation free survival rate in both arms at 12 months.

l “Clinically-driven” target lesion revascularization (TLR) rate at 12 months.

EURO CANAL Study European study of POBA versus Cotavance

Paclitaxel Coated Balloon for Infrapopliteal Lesions in CLI.

PI Zeller T: Investigator Initiated

Leipzig DEB BTK Registry

A.Schmidt et al. JACC 2011

Singe center Registry of IN.PACT Amphirion for long BTK lesions / occlusions

Prim. Endpoint: 3m Angio Rest. Rate

• 104 patients Angio subgroup: – CLI = 82.6% – Diabetics = 73% – Avg Lesion length = 173 ± 87 mm – Tot Occlusions = 61.9%

DEB (angio subgroup)

PTA* (historical group)

3m Angiographic FU Restenosis (>50%) 27.4% 69%

Full-segment Resten. 10% 56%

Restenosis Length 64 mm 155 mm

12m Clinical FU

15m Clinical FU

Deaths 16.3% 10.5%

Limb Salvage 95.6% 100%

Clinical Improvement (1) 91.2% 76.5%

Compl. wound healing 74.2% 78.6%

TLR 17.3% 50%

27.4% angiographic Restenosis Rate at 3 months with 17.3 TLR rate at 12

months

F.Liistro LINC 2012

Single center RCT of IN.PACT Amphirion vs. PTA in BTK-CLI-DIABETICS de-novo lesions • Prim. Endpoint: 12m Angio Restenosis Rate

• 120 patients (preliminary results) • Baseline (DEB vs. PTA): • CLI = 100%

• Diabetics = 100%

• Mean lesion length = 121 ± 83 vs. 123 ± 68 (p=ns)

• Tot Occlusions = 80% vs. 82% (p=ns)

• Pre-dilat. = 100%

DEBATE Randomized Trial

29%

14%

72%

50%

0%

25%

50%

75%

100%

Restenosis Reocclusion

DEB

PTA

12-month FU Angio: 81% (DEB) / 89% (PTA)

Duplex: 18% (DEB) / 11% (PTA)

P=0.0004

P=0.0006

PTA DEB

IN.PACT significantly reduces Restenosis Rate at 12-month vs. PTA in

BTK-CLI-Diabetics

DEBATE- BTK Randomized Trial

Single center RCT of IN.PACT vs. PTA in MULTILEVEL lower limb disease Prim. Endpoint: 6m LLL •  50 patients

•  Fempop / BTK = 76% / 24% •  IC / CLI = 62% / 38%

DEBELLUM Randomized Trial

IN.PACT shows reduction of restenosis vs. PTA in multilevel (SFA + BTK)

disease with and without Stent

Drug Eluting Balloon Evaluation for Lower Limb mUltilevel treatMent

F.Fanelli LINC 2012

IN.PACT™ Peripheral Clinical Trial Program

AV-F

istu

las

B

TK

SFA

-ISR

SFA

de-n

ovo

23 Trials (14 RCT) / 4000+ Patients

Localised Drug Delivery: Mechanism of Action

Mechanism of Drug Transfer of PCB Acute Tissue Transfer of Paclitaxel

Localised Drug Delivery: Animal Data

Paclitaxel Delivery To Vessel Wall Using a DCB: PACCOCATH® (iopramide)

Taxus Uncoated Balloon

Cypher Coated Balloon

Taxus Uncoated Balloon

Cypher Coated Balloon

Taxus

Uncoated Balloon

Cypher Coated Balloon

7 Days

28 Days

90 Days

Single revascularisation Repeat revascularisation

Dick F et al 2007;45:751-761

Repeat Interventions: Diabetics

Limited clinical efficacy of single vs. repeat PTA in diabetics

Sus

tain

ed c

linic

al s

ucce

ss

Sec

onda

ry c

linic

al s

ucce

ss

QoL & Cost of Amputation

Rogers L et al. Journal of the American Podiatric Medical Association 2008;98:166-186

Medical Outcome Study Short Form 36 (0-100)

Boutoille D et al. Foot and ankle international 2008;29:1074-1078

Company DCB STATUS DRUG EXCIPIENT Biotronik Passeo (18) Lux

Awaiting CE mark

Paclitaxel BTHC*

COOK Advance 18 PTX Available Paclitaxel Undisclosed Eurocor Freeway 0.014” Available Paclitaxel Shellac (resin) Lutonix (BARD)

Moxy CE Mark granted

Paclitaxel Undisclosed

Medrad Cotavance 0.014” Available Paclitaxel Ultravist 370 (contrast)

Medtronic/Invatec

INPACT Amphirion 0.014”

Available Paclitaxel Urea

Currently Available & Proposed DCBs (BTK Application)

*BTHC=Butyryl-tri-hexyl Citrate

(an additive in blood bags to keep the crystalline structure of

the plastic malleable – it degrades to citric acid & alcohol)

Medtronic InPact BTK Clinical Trial Program:

Zeller T

Wound Healing Time:

Rogers LC et al. Podiatry Care, Chapter 113, Rutherford’s Vascular Surgery 7th Edition, Cronenwett JL, Johnston KW, Elsevier Inc, 2012

BTK “Standard Angioplasty In Critical Limb Ischaemia

“ Reintervention is an inevitable part of the treatment of CLI patients with BTK lesions using POBA ”

Fernandez N et al JVS 2010;52:834-842

1-Year Patency In Limbs Undergoing Tibial Interventions

N = 121

BLUE = 10 patency

RED = Assisted 10 patency (additional endo. procedures)

RED = 20 patency (additional endo. procedures)

Wound Healing Time:

Zeller T

The Evidence-Base For DCB BTK: Registry Data:

Drug Coated Balloons for BTK angioplasty:

1-Year Results From A single Centre Registry

Popusoi G et al TCT 2012

N = 75

Medtronic InPact Amphirion

Rutherford Class Number (%)

3 4 (5)

4 24 (30)

5 37 (50)

6 10 (6)

Drug Coated Balloons for BTK angioplasty:

1-Year Results From A single Centre Registry

Popusoi G et al TCT 2012

Mean Lesion Length : 89 +/- 25 mm

Total Occlusions : 47%

Drug Coated Balloons for BTK angioplasty:

1-Year Results From A single Centre Registry

Popusoi G et al TCT 2012

12-Month Angiographic Restenosis 24 (n = 15)

9 underwent re-intervention (symptomatic)

12-Month 10 Patency = 76% (n=52)

12-Month 20 Patency = 91% (n=61)

IN.PACT DEEP PIs Iris Baumgartner; Dierk Scheinert; Thomas Zeller

Construct Multicenter randomized (2:1) DEB vs PTA

Population CLI Setting 357 / 15 EU Endpoints 12m LLL (Angio cohort)

12m TLR (all AFS surviving patients) Al cause death major amputation and TLR at 6m

Follow Up Schedule

30d, 3m, 6m, 1y, 2y, 3y, 4y, 5y

objective wound assessment

Enrolment Completed N = 357

Fanelli F et al JEVT 2012;19:571-580

Study design

6-Month Late Lumen Loss:

*

*Primary stenting (SFA only, no pre-dilatation)

*Bail out stents (flow limiting dissection/>50% residual stenosis) ineligible

*In-stent restenosis: an exclusion criterion

P < 0.01 P < 0.01

Wound Healing Time (DEFINITIVE LE BTK Cohort):

N = 70

Rutherford 4 - 6

Zeller T