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

Clinical trial overview DIORII technology Clinical trial overview Key lessons learned

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: Inflation time and PTX tissue delivery 45 min post-dilation (µM/L) Homogenous tissue delivery Penetration depth up to 2mm Measurable plasma PTX found only after 60sec inflation (µM/L) 12 h post-dilation Optimal inflation 30-45s Posa et al. Catheter Cardiovasc Interv 2010 ;76(3):395-403

Clinical trial 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): dilatation pressure just above nominal Inflation time 30- 45 seconds (DIOR-II) Angiographic success: final residual lesion stenosis <30% in the target lesion

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, 14th-23rd 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

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

Results: BMS vs. DES All P=NS

Spanish DIOR Registry: n=250 01/16/11 Spanish DIOR Registry: n=250 In-stent restenosis (126 pts) Bifurcations excluding ISR or small vessels (21 pts) De novo lesions in small vessels (<2.5mm) (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.

Spanish DIOR Registry: n=250 01/16/11 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.

Unless specified otherwise, values are % and (n) of patients 01/16/11 Pre-dilatation (plain balloon) 100% Diameter, mm (meanSD) 2.6+/-0.5 Length, mm (meanSD) 14.3 +/-4.5 Dior Balloon 2.9+/-0.4 19.2+/-5.5 Main balloon pressure, mmHg, (meanSD) 14.6+/-3.4 1st Generation of Dior 69.0 (87) Unless specified otherwise, values are % and (n) of patients

Clinical outcome 1 month 12 month* Overall Death (2) 1.6 (7) 5.8 01/16/11 Clinical outcome 1 month 12 month* Overall Death (2) 1.6 (7) 5.8 Cardiac death (1) 0.8 (5) 4.0 Non-cardiac MI TLR (15) 11.9 MACE** (21) 16.7 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 01/16/11 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 6mo 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 1.35 0.33 Late loss (MLD post-MLD 6m FU) 0.31±0.28

ISR pattern Ic - Focal Body (<10mm). 01/16/11 ISR pattern Ic - Focal Body (<10mm). Before DIOR Follow up angio at 6 m 1c TLR= 9.4%

Spanish DIOR Registry: n=250 01/16/11 Spanish DIOR Registry: n=250 De novo lesions in small vessels (<2.5mm) (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.

Unless specified otherwise, values are % and (n) of patients 01/16/11 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, mmHg (meanSD) 12.2 3.3 Dior Balloon 2.20.2 20.25.3 Main balloon pressure, mmHg, (meanSD) 12.83.3 1st Generation of Dior 54.4 (56) Inflation time (sec). (meanSD) 105.553.2 Post-dilatation 4.9 (5) Unless specified otherwise, values are % and (n) of patients

92.5% (86) (7 coronary disection > type B) 01/16/11 SV: clinical outcome Angiographic success 92.5% (86) (7 coronary disection > type B) Death % (n) 2.9 (3) Cardiac Non-cardiac 0 (0) MI % (n) 1.0 (1) TLR (%) MACE† (%) 5.8 (6) Thrombosis (%) 1.0 (1)* Median FU 12 months (7.8-13.1) *Subacute occlusion Cumulative Non hierarchical MACE

Unless specified otherwise, values are mm (mean±SD) 01/16/11 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 Post-PCI 6mo FU Reference diameter 1.990.34 Lesion length 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 Acute Gain 1.11 0.30 Late loss (MLD post-MLD 6m FU) 0.34±0.23 Binary Restenosis, (n) % 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) Sequential MB/SB dilatation with DEB Provisional T-stenting with BMS Provisional T-stenting with BMS Provisional T-stenting with DES Kissing balloon with regular balloons Kissing balloon with regular balloons Kissing balloon with regular balloons 3-month dual anti-platelet therapy 3-month dual anti-platelet therapy 12-month dual anti-platelet therapy Stella P et al

Results Angiographic follow-up at 6 months DEB+BMS N=40 BMS N=37 DES P Value DEB vs. BMS Late luminal loss, mm 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 Lower than expected 0.11 ± 0.43 0.92 Binary restenosis 2 (6.1%) 5 (14.3%) 2 (5.4%) 0.24 5 (15.2%) 6 (17.1%) 0.82 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: Stella P, TCT 2011 Primary PCI for STEMI Thrombobectomy (TIMI > 1) Randomization DEB + BMS BMS DES 6-month clinical and angiographic FU 6-month clinical and angiographic FU 6-month clinical and angiographic FU OCT+Acethylcholine endothelial testing OCT+Acethylcholine endothelial testing OCT+Acethylcholine endothelial testing Stella P, TCT 2011

Results: Angiographic 6-month follow-up DEB+BMS N=42 BMS DES N=43 P Value DEB vs. BMS 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 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 0.99 Stent thrombosis (4 and 5 days) 2 (4.0%) 0.15 Major adverse cardiac events 12 (23.5%) 2 (4.1%) 0.67

Importance of pre-dilatation in DEB

OCT results at follow up   DEB+BMS N=12 BMS N=10 DES P Value DEB vs. BMS 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, mm2 3.21±2.06 3.46±1.92 5.76±1.89 0.79 0.01 Mean lumen area, mm2 5.69±2.36 5.90±2.43 8.06±1.34 0.86 0.02 Maximum neointimal area, mm2 4.90±0.88 6.74±2.69 2.96±1.28 0.06 0.001 Mean neointimal area, mm2 2.86±0.89 4.14±1.61 1.32±0.58 0.05 <0.001 Lumen volume, mm3 132.0±54.7 151.2±75.6 173.2±74.7 0.54 0.19 Stent volume, mm3 197.6±67.2 259.6±114.1 202.7±96.6 0.17 0.90 Neointimal volume, mm3 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 0.38 0.85 Malapposed struts, % 1.74±2.08 0.56±1.40 3.47±3.62 0.22

DEAR Registry - Flow 91 pts (33.1%) included 106 lesions; 60% LAD 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 2.5mm diameter, length 24.8mm DIOR+BMS =96%; DIOR=4%

DEAR Registry – Clinical outcome at 12m 13.2 % 10.9 % 8.3 % 6.6 % 3.3 % 2.2 % 2.2% 1.1 %

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

Valentine II case: Initial

DIOR II (after predilatation)

Immediate result

8mth follow up

DIOR-II Key lessons learned

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

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) 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 ~30days helps re-endothelialization and reduces required duration of antiplatelet therapy Absence of permanent polymer: avoids chronic inflammation Absence of a permanent stent: preserves original vessel anatomy (e.g. bifurcation, tortuosity) avoid double/triple metal layers (e.g. ISR or bifurcation) easier initial device tracking and easier re-cross avoids risk of stent fracture (e.g. at tortuosity)