Neointimal Modification with Scoring-Balloon and Efficacy of Drug-Coated Balloon Therapy in Patients with Restenosis in Drug- Eluting Coronary Stents Deutsches Herzzentrum München & I. medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, both Munich; Herzzentrum der Segeberger Kliniken Gruppe, Bad Segeberg; Krankenhaus Landshut-Achdorf, Medizinische Klinik I, Landshut; all in GERMANY Robert A. Byrne, Sebastian Kufner, Michael Joner, Simon Schneider, Ralph Tölg, Janika Repp, Erion Xhepa, Tareq Ibrahim, Salvatore Cassese, Massimiliano Fusaro, Ilka Ott, Christof Burgdorf, Christian Hengstenberg, Heribert Schunkert, Bernhard Zrenner, Gert Richardt, Karl-Ludwig Laugwitz, Adnan Kastrati ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Neointimal Modification with Scoring-Balloon and Efficacy of Drug-Coated Balloon Therapy in Patients with Restenosis in Drug- Eluting Coronary Stents ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 ISAR-DESIRE 4

Disclosure Statement of Financial Interest I, Robert A. Byrne, have received lecture fees from: B. Braun Melsungen AG Biotronik Boston Scientific ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Drug-coated balloon therapy Byrne et al. | Treatment of In-stent Restenosis In: Interventional Cardiology - A Companion to Braunwald's Heart Disease Drug-coated balloon angioplasty for the treatment of coronary drug-eluting stent restenosis has demonstrated encouraging results and has the advantage of avoiding additional stent layers in restenotic lesions

Background Gold text can be used as a highlight color  No text shadows on any text Italics are better to emphasize words rather than underline Line spacing should be 1 Line with 0.3 before each paragraph Set the slide transition to wipe right Remove unnecessary animations The efficacy of DCB treatment relies on rapid initial drug transfer and tissue retention of the anti-proliferative drug Neointimal modification with scoring balloon pre-dilation may enhance the efficacy of DCB therapy ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Study Objective To compare the anti-restenotic efficacy of: Scoring balloon pre-dilation before paclitaxel-coated balloon therapy Versus Standard balloon pre-dilation before paclitaxel-coated balloon therapy in patients with limus-DES restenosis ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Study Devices ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 Pantera Lux paclitaxel-coated balloon Angiosculpt scoring balloon 3 µg paclitaxel/mm2 Butyryl-tri-hexyl citrate (BTHC) excipient Balloon with 3 nitinol spiral “scoring” wires (~0.005”) Spectranetics Biotronik

Study Organization Design 252 patients with DES-restenosis enrolled between June 2012 and December 2014 in 4 centers in Germany Angiographic follow-up at 6-8 months in 80.4% (N=203)* Clinical follow-up at 12 months Standard balloon plus paclitaxel- coated balloon (N=127) Scoring balloon plus paclitaxel- coated balloon (N=125) *no significant differences across groups ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 DESIGN: Prospective, randomized, active controlled, multicenter clinical trial INCLUSION CRITERIA: 1.Stenosis > 50% in “limus”- eluting DES 2.Symptoms/signs of ischemia EXCLUSION CRITERIA: 1.Lesion in left main stem 2.Acute STEMI 3.Cardiogenic shock FUNDING: Biotronik

Study Organization Design ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 PRIMARY ENDPOINT: Percent diameter stenosis at follow- up angiography TEST HYPOTHESES: neointimal modification with scoring balloon pre-dilation before DCB would be superior to standard balloon pre-dilation before DCB %DS= 26.25% vs. 35% 2-sided α-level = 0.05 power = 80% 101 patients per group 252 patients with DES-restenosis enrolled between June 2012 and December 2014 in 4 centers in Germany Angiographic follow-up at 6-8 months in 80.4% (N=203)* Clinical follow-up at 12 months Standard balloon plus paclitaxel- coated balloon (N=127) Scoring balloon plus paclitaxel- coated balloon (N=125) *no significant differences across groups

Results ISAR-DESIRE 4 ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Baseline Characteristics Scoring balloon N = 125 Control N = 127 Age, years 69.4 Female Diabetes mellitus Multivessel disease ACS Patients No significant differences across groups ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Baseline Characteristics Scoring balloon N = 125 Control N = 127 ISR Morphology, % Focal Diffuse Proliferative Occlusive Lesions ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 No significant differences across groups

Baseline Characteristics Scoring balloon N = 125 Control N = 127 Stent type, % biolimus-eluting everolimus-eluting sirolimus-eluting zotarolimus-eluting Lesions ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 No significant differences across groups

Baseline Characteristics Scoring balloon N = 125 Control N = 127 Vessel size (mm) Stenosis, pre (%) MLD, pre (mm) Stenosis, post (%) MLD post (mm) Procedure ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 No significant differences across groups

Primary Endpoint Diameter Stenosis at Follow-up Angiography ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis Diameter Stenosis at Follow-up Angiography (%) Cumulative Frequency (%) Scoring-balloon Control P= % ± % ± 16.8

Secondary Endpoint Target Lesion Revascularization Binary Restenosis P =0.03P = 0.25 Scoring balloon Control % Scoring balloon Control ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Secondary Endpoint Death/Myocardial Infarction Months After Randomization Death or Myocardial Infarction (%) P> 0.99 Scoring-balloon Control Scoring Balloon 3.3% Control 3.4%

Secondary Endpoint Target Lesion Thrombosis % Scoring balloon Control ISAR-DESIRE 4: Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4

Conclusions In patients presenting with DES restenosis… paclitaxel-coated balloon based strategies confirmed a high clinical safety profile out to 1 year neointimal modification with scoring- balloon significantly improves the angiographic antirestenotic efficacy of paclitaxel-coated balloon angioplasty

Intracoronary Stenting and Angiographic Results: Optimizing Treatment of Drug Eluting Stent In-Stent Restenosis 4 ISAR-DESIRE 4 Thank You