Current Results of Drug Coated Balloons for Infrapopliteal Disease Kenneth Rosenfield, MD Massachusetts General Hospital Boston, Massachusetts

Kenneth Rosenfield, MD Consulting: Complete Conference Management, AngioDynamics, Inc., Bard Peripheral Vascular, Inc. and The Medicines Company. Grant Support: Atrium Medical Corporation, Abbott Laboratories, Cordis Corporation, IDEV Technologies, Inc., Lutonix, Inc. and Bard Peripheral Vascular, Inc. Honoraria: VIVA Physicians Stocks, Stock Options, other ownership interest: VORTEX, ICON Interventional Systems, Medical Simulation Corporation, Contego and CardioMEMS, Inc. Off-Label: May discuss off-label use of devices occasionally employed in carotid revasc.

The Implications of CLI “We often see a man pass away by degrees, and limb by limb lose the sensation of life: first the toes of the feet grow livid, next die the feet and legs, afterwards over the other limbs go creeping the cold footsteps of death...” -Leviticus (96-55 BC)

Infrapopliteal Intervention Indications Treat Ischemic rest pain Facilitate healing of ulcer/gangrene (where foot is salvageable Lower level of amputation Facilitate healing of amputation site Treat severe claudication that interferes with ADL’s “Less certain” Treat moderate life-style limiting claudication Provide better outflow to maintain proximal device patency

Infrapopliteal Intervention Defining success Elimination of pain Limb healing and salvage Improved ambulation Improved functional status Improved quality of life Reduced mortality Relationship angiographic patency to above?

Infrapop Intervention Achieving goals and measuring outcome Requirement for effective wound-healing (generally) Establish continuous, pulsatile, “in-line” flow to the pedal vessels (at least one) Patency must last at least long enough to achieve wound-healing

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

Special Technical Considerations (challenges) for Infrapop Intervention Heavy plaque burden and diffuse nature of disease Small diameter of vessels (diabetics) Calcification Prevalence of occlusions…often lengthy Presence of collaterals (reducing flow in parent vessel) Aggressive restenosis

For Certain Territories, No Matter How Good the Initial Result, Mechanical Treatments Alone Do Not Last 8 mos later – rest pain Laser/PTA Pre Post

DCBs: Why All the Hype? Potential to fulfill unmet clinical needs… Eliminate liability associated with permanent implant Chronic inflammation, stimulus for hyperplasia & ISR Issue of repeat access & subsequent intervention Fracture Treatment of “no-stent” zones Reduce need for anti-platelet therapy (DAPT) Simplicity? Cost reduction? Better safety profile? More practical than stents & other devices for BTK

Drug-Coated Balloon Trials in SFA 6-Month Mean Late Lumen Loss Comparison (median 0.2) (median 1.1) (median 0.3) (median 0.8) LEVANT I THUNDER1 FemPac2 1 Tepe G, et al. N Engl J Med. 2008;358:689–699. 2 Werk M, et al. Circulation. 2008;118:1358 –13565.

DCB: Histopathology Studies Endothelialization complete at 28 days Sustained drug effects in deeper layers through 90 days Little inflammation Healing predominates b/n 90 & 180 days No significance downstream effects …Favorable safety profile!

DCB for BTK: CLI Indication Schmidt et al. Clinical Status: Baseline vs. 1 year 109 limbs 176 +/- 88mm2 27.4% restenosis at 3 months (67% in historic control) 17.3%TLR at 12 months (50% in control) Clinically improved 92% Wound healed 74.2% 95.6% limb salvage 16% mortality Restenosis  focal, when occurred Schmidt, et al. JACC. 2011; 58: 1105-9. Drachman 2-2013

Drug-Device Combinations Drug-coated balloons Balloon alone With cutting balloon With stent With atherectomy Drug-eluting stents Biodegradable stents (+/- drug) Device-delivered cell therapy

Upcoming Trials: Atherectomy and Drug-Coated Balloon Angioplasty in Treatment of Long Infrapopliteal Lesions (ADCAT) Sponsor:Herz-Zentrums Bad Krozingen (PI’s: Aljoscha Rastan Thomas Zeller) Single-center, prospective, randomized study (Bad Krozingen, Germany) 80 subjects (ages 50-85) with long de-novo stenosis (≥6cm) and symptomatic peripheral artery disease (Rutherford 3, 4, or 5) Randomized 1:1 drug-coated balloon angioplasty alone vs. atherectomy plus drug-coated balloon angioplasty Primary endpoint: In-Segment Binary Restenosis, assessed by repeat angiography at 3 months Secondary endpoints: TLR and change in Rutherford-Becker at 6 and 12 mos Follow-up visits 3, 6, 12 months.

DCB for BTK: Conclusions Proven “class” effect Drug delivery to deep layers after single contact (dependent on good carrier) Punctuated delivery sustained release Appears to be safe…need more data Many potential advantages Reduce restenosis; no stent; avoid DAPT, etc. Initial angiographic and clinical results promising Adoption already high OUS Cost unknown Much more comparative data required