the evidence for drug coated balloons below the kneethe evidence for drug coated balloons below the...
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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