1. 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

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

3. Clinical trial overview
DIORII technology
Clinical trial overview
Key lessons learned

4. 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:

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

6. 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):

7. Clinical trial overview
In-stent restenosis
Small vessels
Bifurcations
AMI
De-novo large vessels

8. 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 seconds (DIOR-II)
Angiographic success:
final residual lesion stenosis <30% in the target lesion

9. 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 CRT)
Online-CRF, data management and statistical analysis performed by MEDSTAR

10. 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

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

12. Results: BMS vs. DES
All P=NS

13. 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):
Vaquerizo B, Serra A et al. In preparation 2012.

14. 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):
Vaquerizo B, Serra A et al. In preparation 2012.

15. 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

16. 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 ( ) months
†Definite and probable ST (ARC)
**Cumulative Non hierarchical MACE

17. 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

18. 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%

19. 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):
Vaquerizo B, Serra A et al. In preparation 2012.

20. 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

21. 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 ( )
*Subacute occlusion
Cumulative Non hierarchical MACE

22. 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)

23. 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

24. 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

25. 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

26. 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

27. Importance of pre-dilatation in DEB

28. 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

29. 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%

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

31. 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

32. Valentine II case: Initial

33. DIOR II (after predilatation)

34. Immediate result

35. 8mth follow up

36. DIOR-II
Key lessons learned

37. 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.

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

41. 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)