The Evidence for Drug Coated Balloons Below The Knee:

Transcription

1 The Evidence for Drug Coated Balloons Below The Knee: Dr Sumaira Macdonald MBChB (Comm.), FRCP, FRCR, PhD, EBIR Consultant Vascular Radiologist & Honorary Clinical Senior Lecturer, Freeman Hospital, Newcastle, UK SITE 2013

2 Disclosures: Research / Educational Grants & / or consultancy: Abbott Vascular CR Bard Biotronik Bridgepoint / EPS vascular Cordis (J & J) COOK Ev3/Covidien Medtronic / Invatec Merit Medical Silk Road Medical St Jude/AGA Spectranetics Tryton Medical Pyramed Terumo Vascular Perspectives Volcano WL Gore

3 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)

4 The Natural History of CLI, & Cost Considerations:

5 Natural History of Critical Limb Ischaemia N=136 54% mortality & 46% amputation rate in unreconstructed CLI at 1 year Lepäntalo et al: EJVES 1996;11 (2):

6 QoL & Cost of Amputation Estimated 2007 costs Potential Annual Cost Savings (billions) Rogers L et al. Journal of the American Podiatric Medical Association 2008;98:

7 The Relationship Between Patency & Limb Salvage:

8 Outcomes after PTA in CLI N = 111 (all vessel segments): Kudo T et al. JVS 2005;41:

9 Tissue healing paradigms

10 Is long term patency needed for ulcer healing? Optimal vascularisation Patent Vascularisation Metabolic need Trauma Revascularisation Restenosis Vermassen F 2010 Time needed for healing

11 Is long term patency needed for ulcer healing? Optimal vascularisation Patent Vascularisation Metabolic need Trauma Revascularisation Restenosis New trauma Vermassen F 2010 Time needed for healing

12 Optimal Vs. Suboptimal Perfusion: Durable perfusion is an insurance policy against ulcer recurrency and recrudescence Sub-optimal perfusion renders tissues vulnerable

13 Wound Healing Time: 1. Xcell Trial Rocha Singh Soderstrom JVS Soderstrom EJVES Hoffman EJVES 2007* 5. Chung JVS 2006 Average Time To Healing=6-12 Months (endo/hybrid) *Complete ulcer healing=60-80%

14 The Evidence-Base For DCB BTK: Registry Data:

15 Fist Experience With Drug-Eluting Balloons In Infrapopliteal Arteries: Restenosis Rate & Clinical Outcomes (Leipzig Registry) Schmidt A et al. JACC 2011;58:

16 Clinical Review at 12.5 Months Schmidt A et al. JACC 2011;58:

17 Single Unit Data: DCB Against Historical Controls N = 77* N = 104** Schmidt A et al. Cath Cardiovasc Intervent 2010;76: * Schmidt A et al. JACC 2011;58: **

18 Restenosis Type: 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%

19 Risk-Factors For Restenosis After DCB PTA:

20 The Evidence-Base For DCB BTK: Randomized Trials:

21 DEBATE- BTK Randomized Trial Medtronic InPact Amphirion Liistro F et al TCT 2011/LINC 2012

22 Angiographic & Procedural Characteristics

23 Clinical & Angiographic Outcome: * * * Randomisation after lesion crossing

24 12-Month Binary Restenosis & Reocclusion:

25 Study design Fanelli F et al JEVT 2012;19:

26 Lesion Characteristics:

27 P < Month Late Lumen Loss: 0.5 +/- 1.4mm (DCB) Vs /- 1.7mm (PTA)

28 Secondary Endpoints (6 Months): P < 0.001* *Clinically and angiographically driven TLR

29 Clinical Outcomes: * P < 0.05 compared to pre-procedure values P < 0.05 PTA Vs. DCB

30 Standard PTA in BTK: Restenosis & TLR Rates D. Sheinert JACC 2012;60: H.K Soder JVIR 2000;11: F Bauman JVIR 2011;22: F Liistro TCT 2012 A Schmidt Cathet Cardovasc Intervent 2012;76: F Fanelli JEVT 2012;19:

31 DCB PTA in BTK (InPact): Restenosis & TLR Rates F Fanelli JEVT 2012;19: A Cioppa JEVT 2012;19: F Liistro TCT 2012 K Suzuki LINC AP 2012 A Schmidt JACC 2011;58:

32 Conclusions: 6/12 biologic data alone are not compelling Early data (12 month patency & TLR) are promising: follow up/consolidation needed Lesion lengths representative (real world) Failure to show amputation advantage over PTA Underpowered for clinical endpoints

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34 Conclusions: Drug Coated Balloons: 6/12 biologic data alone are not compelling Early data (12 month patency) promising: follow up/consolidation needed Consistent class effect - paclitaxel Lesion lengths representative (real world)

35 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

36 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

37 MedRad Cotavance: EURO CANAL & CANAL US

38 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

39 EuroCor: Freeway :

40 Full Drug Jacket Prospective multicentre, non-randomised observational registry CLI *Lesion length 28 cm two balloon overlap maximally N = 100 Enrolment start: Q1/2012 Enrolment finish: Q4/2013 CI Manzi M et al

41 Current DCB paclitaxel dosing DCBs Balloon Surface Dosing Product Paclitaxel (µg/ mm 2 ) Dose on Balloon Surface Lutonix 2 Paccocath (Medrad)) IN.PACT (Invatec/ Medtronic) 3 3 Dior -Gen II (EuroCor) 3

42 EURO CANAL Study European study of POBA versus Cotavance Paclitaxel Coated Balloon for Infrapopliteal Lesions in CLI. 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.

43 PI Zeller T: Investigator Initiated

44 Leipzig DEB BTK Registry 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% 27.4% angiographic Restenosis Rate at 3 months with 17.3 TLR rate at 12 months 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% A.Schmidt et al. JACC 2011

45 DEBATE Randomized Trial 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% IN.PACT significantly reduces Restenosis Rate at 12-month vs. PTA in BTK-CLI-Diabetics 100% 75% 50% 25% 0% 12-month FU Angio: 81% (DEB) / 89% (PTA) Duplex: 18% (DEB) / 11% (PTA) P= % 29% Restenosis PTA DEB PTA P= % 50% Reocclusion DEB F.Liistro LINC 2012

46 DEBATE- BTK Randomized Trial

47 DEBELLUM Randomized Trial Drug Eluting Balloon Evaluation for Lower Limb multilevel treatment 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% IN.PACT shows reduction of restenosis vs. PTA in multilevel (SFA + BTK) disease with and without Stent F.Fanelli LINC 2012

48 IN.PACT Peripheral Clinical Trial Program 23 Trials (14 RCT) / Patients AV-Fistulas BTK SFA-ISR SFA de-novo

49 Localised Drug Delivery: Mechanism of Action

50 Mechanism of Drug Transfer of PCB Acute Tissue Transfer of Paclitaxel

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52 Localised Drug Delivery: Animal Data

53 Paclitaxel Delivery To Vessel Wall Using a DCB: PACCOCATH (iopramide) Uncoated Balloon Coated Balloon Taxus Cypher 7 Days Uncoated Balloon Coated Balloon Taxus Cypher 28 Days 90 Days Uncoated Balloon Coated Balloon Taxus Cypher

54 Repeat Interventions: Diabetics Single revascularisation Repeat revascularisation Sustained clinical success Secondary clinical success Limited clinical efficacy of single vs. Dick F et al 2007;45: repeat PTA in diabetics

55 QoL & Cost of Amputation Rogers L et al. Journal of the American Podiatric Medical Association 2008;98:

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57 Medical Outcome Study Short Form 36 (0-100) Boutoille D et al. Foot and ankle international 2008;29:

58 Currently Available & Proposed DCBs (BTK Application) Company DCB STATUS DRUG EXCIPIENT Biotronik Passeo (18) Lux Awaiting Paclitaxel BTHC* CE mark COOK Advance 18 PTX Available Paclitaxel Undisclosed Eurocor Freeway Available Paclitaxel Shellac (resin) Lutonix (BARD) Moxy CE Mark granted Paclitaxel Undisclosed Medrad Cotavance Available Paclitaxel Ultravist 370 (contrast) Medtronic/ Invatec INPACT Amphirion Available Paclitaxel Urea *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)

59 Medtronic InPact BTK Clinical Trial Program:

60 Zeller T

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

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63 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:

64 1-Year Patency In Limbs Undergoing Tibial Interventions N = 121 BLUE = 1 0 patency RED = Assisted 1 0 patency (additional endo. procedures) RED = 2 0 patency (additional endo. procedures)

65 Zeller T Wound Healing Time:

66 The Evidence-Base For DCB BTK: Registry Data:

67 N = 75 Drug Coated Balloons for BTK angioplasty: 1-Year Results From A single Centre Registry Medtronic InPact Amphirion Rutherford Class Number (%) 3 4 (5) 4 24 (30) 5 37 (50) 6 10 (6) Popusoi G et al TCT 2012

68 Drug Coated Balloons for BTK angioplasty: 1-Year Results From A single Centre Registry Mean Lesion Length : 89 +/- 25 mm Total Occlusions : 47% Popusoi G et al TCT 2012

69 Drug Coated Balloons for BTK angioplasty: 1-Year Results From A single Centre Registry 12-Month Angiographic Restenosis 24 (n = 15) 9 underwent re-intervention (symptomatic) 12-Month 1 0 Patency = 76% (n=52) 12-Month 2 0 Patency = 91% (n=61) Popusoi G et al TCT 2012

70 IN.PACT DEEP PIs Construct Population Setting Endpoints Follow Up Schedule Iris Baumgartner; Dierk Scheinert; Thomas Zeller Multicenter randomized (2:1) DEB vs PTA CLI 357 / 15 EU 12m LLL (Angio cohort) 12m TLR (all AFS surviving patients) Al cause death major amputation and TLR at 6m 30d, 3m, 6m, 1y, 2y, 3y, 4y, 5y Enrolment Completed N = 357 objective wound assessment

71 Study design Fanelli F et al JEVT 2012;19:

72 6-Month Late Lumen Loss: P < 0.01 P < 0.01 * *Primary stenting (SFA only, no pre-dilatation) *Bail out stents (flow limiting dissection/>50% residual stenosis) ineligible *In-stent restenosis: an exclusion criterion

73 Wound Healing Time (DEFINITIVE LE BTK Cohort): N = 70 Rutherford 4-6 Zeller T