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New Technologies to Treat Critical Limb Ischemia- (DES, DEB and Beyond) Faisal Latif MD, FSCAI, FACC Director Cardiac Catheterization Lab, VAMC Assistant Professor of Medicine Associate Program Director Cardiology Fellowship Program University of Oklahoma I have No Financial Disclosure Learning Objectives • Enumerate drug-eluting options for CLI • Discuss data on Drug-Eluting options in CLI • Study Impact of therapies on Amputation Surgery vs PTA • 452 patients with severe limb ischemia (25% true CLI) suitable for both surgery and PTA • Randomized to Surgery-first (n=228) vs PTA-first (n=224) • Primary endpoint: Amputationfree survival • Results: – No difference in healthrelated QOL Amputation Free Survival Adam DJ, et al BASIL trial Lancet 2005;366:1925–34 Drug-Eluting Technology for PAD Paclitaxel • Blocks proliferation of SMCs, fibroblasts, and inflammatory cells; blocks ECM secretion • Very lipophilic  binds tissue at the target site and resists wash-out • Diffuses from endothelial surface into medial and adventitial layers of the arterial wall • Deep wall tissue paclitaxel concentration > 10x level of endoluminal source Paclitaxel was identified as the primary drug for DEB because of rapid uptake and prolonged retention Modes of Drug Delivery Hawkins, Hennebry Circ CV Interv 2011;4:297-302 Platforms for Drug Delivery Hawkins, Hennebry Circ CV Interv 2011;4:297-302 Infusion of Paclitaxel Using Irrigation Balloon • Two cases of recurrent restenosis – External iliac artery and SFA • Clearway balloon used to instill paclitaxel after PTA • Results in a longer duration of patency Latif F, Hennebry TA CCI 2008; 72:294–8 In.Pact DCB vs PTA for FP Disease Multicenter EU & US, randomized (2:1), single blinded Rutherford 2-4 Tepe G, et al London April 5, 2014 DEBATE-BTK Mean Lesion Length: 130mm Liistro F et al Circulation 2013;128:615-621 DEB Treatment Protocol AVOID Geographic Miss! DEB Treatment Protocol • • • • • If >1 balloon used, the overlap was >5 mm Inflation time was at least for both DEB and PTA Coronary DES were used as a bailout 80% of the lesions were total occlusions Subintimal recanalization was performed in one fifth Post hoc analysis of restenosis (%) in different subgroups of the study groups Liistro F et al Circulation 2013;128:615-621 DEB vs PTA Liistro F et al Circulation 2013;128:615-621 In.Pact DEEP • Largest DEB study in BTK CLI patients • 358 patients with Rutherford class or higher at 13 European sites • Patients randomized 2:1 to treatment with the IN.PACT Amphirion DEB (n=239) or PTA (n=119) • Baseline clinical, angiographic and wound characteristics were similar across the two groups In.Pact DEEP DEB PTA P-value Clinically-driven TLR 9.2% (18/196) 13.1% (14/107) 0.29 Late Lumen Loss 0.61±0.78 0.62±0.78 0.95 17.7% (41/232) 15.8% (18/114) 0.021 (noninferiority) 0.662 (superiority) Primary efficacy at 12 months Primary safety at 6months All-cause mortality, major amputation, clinically-driven TLR Medtronic voluntarily withdrew the IN.PACT Amphirion DEB from all markets in 11/2013 Infra-genicular DES vs BMS • Everolimus-eluting coronary DES vs BMS for infrapopliteal PAD for CLI • DESTINY Trial • 140 patients at five European sites • Primary end point: Patency at 12 months, defined as the absence of >50% restenosis • 74 patients treated with Xience V and 66 patients were treated with Vision Bosiers M, et al Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive Disease J Vasc Surg 2012;55:390-9.) Primary Patency p=0.001 Freedom from TLR p=0.001 Survival Major amputations rare in both groups, and no difference What’s Missing? Prevention of Amputation Preventing leg amputations in CLI with BTK DES: PARADISE Trial • 106 patients (118 limbs) treated with DES (nonrandomized) • No patients excluded because of comorbidities/anatomy • Primary end points: Major amputation and mortality • Results: – 3-year amputation was 6%; survival was 71%; amputation-freesurvival was 68 +/- 5% • Target limb revascularization in 15% of patients, and repeat angiography in 35% of patients revealed a binary restenosis in 12% Feiring AJ, et al PARADISE Trial JACC 2010;55(15):1580-9 Feiring AJ, et al PARADISE Trial JACC 2010;55(15):1580-9 Observations from PARADISE Trial 3-year limb salvage/freedom from amputation: 94% Wound healing and relief of rest pain: 93% Trend of Improved limb salvage in Rutherford 4/5 vs 6: 97% vs 88% Comparison with BASIL Study (surgery vs PTA): – 90% of screened patients excluded (poor targets) – Only 25% of enrolled patients had CLI Why DEB could be better than DES? • DEB-based drug maintains the anti-proliferative properties • Could be used where DES cannot be delivered • Uptake of paclitaxel by is rapid and retained up to week • Most appealing indication: ISR Sustained drug release is not a requisite for the long-lasting anti-proliferative effect of paclitaxel! Axel DI, et al Circulation 1997; 96: 636–645 Conclusion • Various Drug-eluting technologies hold promise • Above the knee, DES and DEB worked well • Below-the knee, Could DEB prove to be better than DES? • DAPT issues PARADISE trial used lifelong!