Lessons From The DIOR DCB Clinical Trials Dr

Lessons From The DIOR DCB Clinical Trials Dr Ian B. A. Menown MD FRCP Director, Interventional Cardiology, Craigavon Cardiac Centre, N. Ireland Hon. Senior Lecturer, Queen’s University

Relevant disclosures • Clinical trialist: Biosensors, Biotronik, Boston Scientific, Capella, Eurocor, Medtronic, Orbus Neich, Terumo • Conference sponsorship: Abbott, Boston, Biosensors, Eurocor, Medtronic 2

DIORII technology Clinical trial overview Key lessons learned 3

DIOR-II Technology • Shellac coating - well established as a food coating, tablet coating and in cosmetics • CE marked; safety recognised by FDA (GRAS). • Coating method – micropipette administered 1: 1 mixture of Paclitaxel (Ph Eur. ) and Shellac (Ph Eur. ) which results in homogenous surface distribution (<10% variability) • Paclitaxel balloon surface concentration: 3 µg/mm² • Drug hidden within balloon folds – helps protect from guide/proximal vessel wash-off:

$DIOR-II Technology Shellac: high optical refraction (smooth, shiny surface)$

DIOR-II Technology Shellac: high optical refraction (smooth, shiny surface)

DIOR-II: Inflation time and PTX tissue delivery (µM/L) 45 min post-dilation 12 h post-dilation Optimal inflation 3045 s • Homogenous tissue delivery • Penetration depth up to 2 mm • Measurable plasma PTX found only after 60 sec inflation Posa et al. Catheter Cardiovasc Interv 2010 ; 76(3)

overview In-stent restenosis Small vessels Bifurcations AMI De-novo large vessels

Recommended PCI technique • Initial pre-dilatation balloon: – balloon: artery ratio 1: 1 – length 5 mm shorter than that of the DIOR balloon • DIOR dilatation (used to deliver PTX to the vessel wall): – balloon: artery ratio 1: 1 – dilatation pressure just above nominal – Inflation time 30 - 45 seconds (DIOR-II) • Angiographic success: – final residual lesion stenosis <30% in the target lesion 8

Valentines trial I: DIOR in ISR • Multi-centre, international registry study • 276 patients (244 with follow up), 96 centres, 26 countries, 50% on site monitoring • To assess the efficacy of Dior®-II for ISR following BMS or DES ISR. • “Snapshot enrollment” during 9 days (starting Valentine’s day, 14 th-23 rd Feb 2010 - CRT) • Online-CRF, data management and statistical analysis performed by MEDSTAR

Baseline data • • • 1/3 diabetic Lesion location: 40% proximal, 50% LAD Pattern of restenosis: 40% diffuse Mean DIOR diameter (mm) 3. 0 ± 0. 4 Mean DIOR length (mm) 24 ± 9. 1 10

Results: Clinical outcome Between discharge and follow-up (mean 8 months)

Results: BMS vs. DES All P=NS 12

Spanish DIOR Registry: n=250 In-stent restenosis (126 pts) De novo lesions in small vessels (<2. 5 mm) (103 pts ) Bifurcations excluding ISR or small vessels (21 pts) Vaquerizo B, Serra A et al. J Interv Cardiol. 2011; 24(6): 518 -28. Vaquerizo B, Serra A et al. In preparation 2012.

Spanish DIOR Registry: n=250 In-stent restenosis (126 pts) Diabetes 33% ACS 51% ≥ 2 vessel disease 60% Vaquerizo B, Serra A et al. J Interv Cardiol. 2011; 24(6): 518 -28. Vaquerizo B, Serra A et al. In preparation 2012.

• Pre-dilatation (plain balloon) Diameter, mm (mean SD) Length, mm (mean SD) • Dior Balloon Diameter, mm (mean SD) Length, mm (mean SD) Main balloon pressure, mm. Hg, (mean SD) 1 st Generation of Dior Unless specified otherwise, values are % and (n) of patients 100% 2. 6+/-0. 5 14. 3 +/-4. 5 2. 9+/-0. 4 19. 2+/-5. 5 14. 6+/-3. 4 69. 0 (87)

Clinical outcome 1 month 12 month* Overall Death (2) 1. 6 (7) 5. 8 Cardiac death (1) 0. 8 (5) 4. 0 Non-cardiac (1) 0. 8 (2) 1. 6 MI (1) 0. 8 (5) 4. 0 TLR (1) 0. 8 (15) 11. 9 MACE** (2) 1. 6 (21) 16. 7 0 (1) 0. 8 ST† (ARC) *Median of FU 11. 95 (5. 9 -13. 5) months †Definite and probable ST (ARC) **Cumulative Non hierarchical MACE

QCA and Restenosis • • • Angiographic follow-up at a mean of 6. 5± 2. 1 months In 2 centers (79. 1% FU completed) 34 patients (27% of the overall population with angio FU) Pre-PCI Post-PCI 6 mo FU Reference diameter 2. 6 0. 5 Lesion length 14. 4 7. 5 MLD 0. 77 0. 49 2. 12 0. 48 1. 81 0. 74 Diameter stenosis % 76. 7 14. 2 19. 1 8. 7 34. 6 23. 4 Acute Gain Late loss (MLD post-MLD 6 m FU) 1. 35 0. 33 0. 31± 0. 28

ISR pattern Ic - Focal Body (<10 mm). Before DIOR Follow up angio at 6 m 1 c TLR=

Spanish DIOR Registry: n=250 De novo lesions in small vessels (<2. 5 mm) (103 pts ) Vaquerizo B, Serra A et al. J Interv Cardiol. 2011; 24(6): 518 -28. Vaquerizo B, Serra A et al. In preparation 2012.

SV: procedure Pre-dilatation (plain balloon) ALL Diameter, mm (mean SD) 2. 01 0. 3 Length, mm (mean SD) 15. 9 4. 1 Main balloon pressure, mm. Hg (mean SD) 12. 2 3. 3 Dior Balloon Diameter, mm (mean SD) 2. 2 0. 2 Length, mm (mean SD) 20. 2 5. 3 Main balloon pressure, mm. Hg, (mean SD) 12. 8 3. 3 1 st Generation of Dior 54. 4 (56) Inflation time (sec). (mean SD) Post-dilatation 105. 5 53. 2 4. 9 (5) Unless specified otherwise, values are % and (n) of patients

SV: clinical outcome Median FU 12 months (7. 8 -13. 1) Angiographic success 92. 5% (86) (7 coronary disection > type B) Death % (n) 0 2. 9 (3) Cardiac 0 2. 9 (3) Non-cardiac 0 0 (0) MI % (n) 0 1. 0 (1) TLR (%) 0 2. 9 (3) MACE† (%) 0 5. 8 (6) Thrombosis (%) 0 1. 0 (1)* *Subacute occlusion Cumulative Non hierarchical MACE

SV: QCA and restenosis • • Angiographic follow-up at a mean of 7. 5± 2. 6 months 2 centers (49. 5% of the overall population) N=51 Pre-PCI Reference diameter 1. 99 0. 34 Lesion length Post-PCI 6 mo FU 14. 7 7. 1 MLD 0. 46 0. 28 1. 56 0. 32 1. 22 0. 53 Diameter stenosis % 79. 5 13. 4 23. 8 10. 2 39. 6 26. 1 1. 11 0. 30 Acute Gain Late loss (MLD post-MLD 6 m FU) Binary Restenosis, (n) % 0. 34± 0. 23 10/51 (19. 6%) Unless specified otherwise, values are mm (mean±SD)

DEBUIT bifurcation study Randomized patients (n=117) Sequential MB/SB dilatation with regular balloon Randomization DEB (n=40) BMS (n=37) DES (n=40) Provisional Tstenting with BMS Provisional Tstenting with DES Kissing balloon with regular balloons 3 -month dual antiplatelet therapy 12 -month dual antiplatelet therapy Sequential MB/SB dilatation with DEB Stella P et al

Results Angiographic follow-up at 6 months P Value DEB+BMS DES N=40 N=37 N=40 Proximal main branch 0. 58 ± 0. 65 0. 60 ± 0. 65 0. 13 ± 0. 45 0. 87 Distal main branch 0. 41 ± 0. 60 0. 49 ± 0. 85 0. 19 ± 0. 64 0. 67 Side branch 0. 19 ± 0. 66 0. 21 ± 0. 57 0. 11 ± 0. 43 0. 92 DEB vs. BMS Late luminal loss, mm Lower than expected Binary restenosis Proximal main branch 2 (6. 1%) 5 (14. 3%) 2 (5. 4%) 0. 24 Distal main branch 5 (15. 2%) 6 (17. 1%) 2 (5. 4%) 0. 82 Side branch 7 (21. 2%) 7 (20%) 3 (8. 1%) 0. 90 Overall bifurcation restenosis 8 (24. 2%) 10 (28. 6%) 6 (15%) 0. 79

DEB – AMI: Primary PCI for STEMI Thrombobectomy (TIMI > 1) Randomization DEB + BMS DES 6 -month clinical and angiographic FU OCT+Acethylcholine endothelial testing Stella P, TCT 2011

Results: Angiographic 6 -month follow-up P Value DEB vs. BMS DEB+BMS N=42 DES N=43 Late luminal loss, mm Primary endpoint 0. 64± 0. 56 0. 78± 0. 59 0. 21± 0. 32 0. 25 Minimal luminal diameter, mm 1. 86± 0. 74 1. 68± 0. 75 2. 31± 0. 42 0. 25 Binary restenosis 12 (28. 6%) 11 (26. 2%) 2 (4. 7%) 0. 86 Diameter stenosis, % 35. 7± 20. 9 41. 2± 23. 5 19. 0± 11. 6 0. 26 Target lesion revascularization 10 (20. 0%) 9 (17. 6%) 1 (2. 0%) 0. 76 Target-vessel revascularization 1 (2. 0%) 0. 99 Stent thrombosis (4 and 5 days) 2 (4. 0%) 0 0 0. 15 10 (20. 0%) 12 (23. 5%) 2 (4. 1%) 0. 67 Major adverse cardiac events

Importance of pre-dilatation in DEB

OCT results at follow up DEB+BMS N=12 BMS N=10 DES N=10 P Value DEB vs. BMS P Value DEB vs. DES Stent length analyzed 24. 9± 10. 2 26. 9± 9. 0 22. 42± 11. 5 0. 67 0. 63 Minimum lumen area, mm 2 3. 21± 2. 06 3. 46± 1. 92 5. 76± 1. 89 0. 79 0. 01 Mean lumen area, mm 2 5. 69± 2. 36 5. 90± 2. 43 8. 06± 1. 34 0. 86 0. 02 Maximum neointimal area, mm 2 4. 90± 0. 88 6. 74± 2. 69 2. 96± 1. 28 0. 06 0. 001 Mean neointimal area, mm 2 2. 86± 0. 89 4. 14± 1. 61 1. 32± 0. 58 0. 05 <0. 001 Lumen volume, mm 3 132. 0± 54. 7 151. 2± 75. 6 173. 2± 74. 7 0. 54 0. 19 Stent volume, mm 3 197. 6± 67. 2 259. 6± 114. 1 202. 7± 96. 6 0. 17 0. 90 Neointimal volume, mm 3 65. 6± 28. 1 108. 3± 48. 8 29. 4± 23. 9 0. 03 0. 008 Strut analyses Total no. struts analyzed 5795 3530 4938 0. 85 Malapposed struts, % 1. 74± 2. 08 0. 56± 1. 40 3. 47± 3. 62 0. 06 0. 22

DEAR Registry - Flow April 2009 to March 2011 1. 528 patients underwent PCI in 3 centres from Argentina, of whom 275 (18%) were diabetics PI: Alfredo Rodrigues (Buenos Aires, Argentina) Diabetics, de novo 92 pts consented Inability to cross lesion in one pt 91 pts (33. 1%) included 106 lesions; 60% LAD Mean DIOR 2. 5 mm diameter, length 24. 8 mm DIOR+BMS =96%; DIOR=4%

DEAR Registry – Clinical outcome at 12 m 13. 2 % 10. 9 % 8. 3 % 6. 6 % 3. 3 % 2. 2 % 1. 1 %

DIOR®: ongoing coronary studies Trial Name Investigator Location Start Endpoint Objectives Current Status Publication Link Valentine s Trial II Dres. Serra, Rodriguez, Fazila Worldwid e 14 th Feb – 31 st March 2011 100 Patients De novo Awaiting presentation CRT 2012 001 Trial Dres A. Serra & B. Vaquerizo Worldwid e Spring 2011 50 -60 Patients De Novo Bifurcations Enrolling Magical Pilot Trial Dres Rosli, Stella and Tan Worldwi de Winter 2011 45 -60 Patients De Novo In preparation Europea n Magical Registry Dr Menown European Centers Europe Autumn 2011 100 Patients De Novo Enrolling Indian Magical Registry Dr Kaul Indian Centers India Autumn 2011 100 Patient s De Novo Starting soon Be Safe Trial Dres Fermin and Collet Venezue la Spring 2012 Patients De Novo In preparation 31

Valentine II case: Initial

DIOR II (after predilatation)

Immediate result

8 mth follow up

DIOR-II Key lessons learned 36

Lessons learned 1. Adequate lesion preparation (predilatation) before DIOR important to optimise results 2. Avoid geographic miss – aim to use a DIOR >5 mm longer than the pre-dilated segment 3. New DCB (DEB) designs/coatings/excipients can markedly improve the speed and volume of PTX delivery to the vessel wall. Optimum vessel

Lessons learned 4. Clinical indications Probably useful: – ISR, small vessel Possibly useful: bifurcation, AMI Larger vessel de-novo: under investigation

Potential advantages of DCB (DEB) 1. Short lived homogeneous local drug delivery: – highest drug concentrations in vessel wall at time of injury – Near complete absence of drug in vessel wall by ~30 days helps re-endothelialization and reduces required duration of antiplatelet therapy 2. Absence of permanent polymer: avoids chronic inflammation 3. Absence of a permanent stent: – preserves original vessel anatomy (e. g. bifurcation, tortuosity) – avoid double/triple metal layers (e. g. ISR or bifurcation) 1. easier initial device tracking and easier re-cross 2. avoids risk of stent fracture (e. g. at tortuosity) 41