1. University-Heart Center Freiburg - Bad Krozingen
Definitive Therapies - How to Optimize DCB Outcomes: Lessons from the (Germans) Europeans
Prof. Thomas Zeller, MD
Department Angiology
University-Heart Center Freiburg - Bad Krozingen
Bad Krozingen , Germany

2. Faculty Disclosure Thomas Zeller, MD
For the 12 months preceding this presentation, I disclose the following types of financial relationships:
Honoraria received from: Abbott Vascular, Angioslide, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific Corp., Cook Medical, Cordis Corp., Covidien, Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, VIVA Physicians
Consulted for: Abbott Vascular, Bard Peripheral Vascular, Boston Scientific Corp., Cook Medical, Gore & Associates, Medtronic, Spectranetics, ReCor
Research, clinical trial, or drug study funds received from: 480 biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis Corp., Covidien, Gore & Associates, Abbott Vascular, Medtronic, Spectranetics, Terumo, TriReme, Volcano

3. Balloon Inflation Time
Tip No. 1
Balloon Inflation Time

4. Optimal PTA Inflation Time
Optimizing PTA with prolonged balloon inflations reduces dissection severity and rate & hence need for further intervention
Peripheral PTA: Effect of Short vs Long Balloon Inflation Times on the Morphologic Results1
Inflation Time (sec) 30
180
P-Value
Major dissection (grades 3 or 4) 16 5
.010
Minor or no dissection (grades 1 and 2) 21 32
Further interventions (Stent, repeat dilatation, dilation with larger diameter) 20 9
.017
Residual stenosis (>30%) 12
.097
Complication (embolization, thrombosis) 1 -
Mean ankle-brachial index (before, after intervention)
0.66, 0.87
0.65, 0.84
Inflation times of seconds improve immediate infrainguinal PTA results vs. a short dilation strategy
Significantly fewer major dissections and a modest reduction of residual stenoses are observed
Slide approved in DOC 1B (slide 36) – minimal changes in copy, formatting
Zorger defines “further intervention” pg 356 as “prolonged dilation over a period of 10 minutes, dilation to a larger diameter, and stent placement
1. N. Zorger et al. Peripheral Arterial Balloon Angioplasty: Effect of Short versus Long Balloon Inflation Times on the Morphologic Results. J Vasc Interv Radiol. 2002

5. IN.PACT DEEP vs. CLI Literature
Lowest Restenosis, TLR and Major Amputation in both arms
IN.PACT DEEP
[1] Rocha-Singh KJ et al. Catheter Cardiovasc Interv Nov 15;80(6): ; [2] Bosiers M LINC 2011; [3] Zeller T. LINC 2011; [4] Scheinert LINC 2011
«amputations»
[1] Lejay A et al. Acta Chir Belg. 2009; [2] Romiti M et al. J Vasc Surg. 2008; [3] Adam DJ et al. Lancet. 2005; [4] Rocha-Singh KJ et al. Catheter Cardiovasc Interv. 2012; [5] Scheinert D et al. JACC 2012; [6] Iida et al. EJVEVS 2012

6. Maria Cecilia Hospital
The Drug-Eluting Balloon Superficial Femoral Artery - Long Study: The DEB SFA-LONG Study
Safety and efficacy of the Drug-Eluting Balloon (DEB) for the treatment of the Superficial Femoral Artery (SFA) ischemic vascular disease in symptomatic patients presenting with long lesions: A pilot study
Antonio Micari, MD
GVM Care & Research
Maria Cecilia Hospital
Cotignola (RA) Italy
Micari A., EURO-PCR 2015

7. Lesion Characteristics Total lesion length in mm: mean (range):
The DEB SFA-LONG Study
Lesion Characteristics
CHARACTERISTIC
N=105
Lesion Type
De novo
Restenotic
91.4%
8.6%
Lesion Location
Ostial
Proximal SFA
Middle SFA
Distal SFA
Popliteal 1° Segment
20%
65.7%
96.2%
71.4%
22.9%
Occlusion Rate
49.5%
Target Lesion Disease
Occluded
19%
40%
27.6%
5.7%
Stenotic
41%
50.5%
37.1%
13.3%
Total lesion length in mm: mean (range):
±78.89 ( )
Micari A., EURO-PCR 2015

8. The DEB SFA-LONG Study
Cumulative Probability of not having the combined endpoints of cdTLR and >50% restenosis
89.3%
77.2%
Micari A., EURO-PCR 2015

9. The DEB SFA-LONG Study Results
PROCEDURAL RESULTS
PTA success
84.8%
Flow-limiting dissection
6.7%
Persistent >50% residual stenosis
8.6%
Provisional stenting
10.5%
Total treated length in mm (mean, range)
263.5% ± 84.8
ABI target limb at discharge
0.95 ± 0:10
Micari A., EURO-PCR 2015

10. Procedural Characteristics
IN.PACT GLOBAL LONG LESIONS IMAGING COHORT: Lesion/procedural characteristics
Lesions (N)
164
Lesion Type:
de novo
restenotic (no ISR)
ISR
83.2% (134/161)
16.8% (27/161)
0.0% (0/161)
Lesion Length
26.40 ± 8.61 cm
Total Occlusions
60.4% (99/164)
Calcification
Severe
71.8% (117/163)
19.6% (32/163)
RVD (mm)
4.594 ± 0.819
Diameter Stenosis (pre-treatment)
90.9% ± 14.2
Dissections: 0
37.9% (61/161)
A-C
47.2% (76/161)
D-F
14.9% (24/161)
Device success: successful delivery, inflation, deflation and retrieval of the intact study balloon device without burst below the RBP
Procedure success: residual stenosis of ≤ 50% (non-stented subjects) or ≤ 30% (stented subjects) by core lab (if core lab was not available then the site reported estimate was used)
Clinical success: procedural success without procedural complications (death, major target limb amputation, thrombosis of the target lesion, or TVR) prior to discharge
Procedural Characteristics
Device Success
99.5% (442/444)
Procedure Success
99.4% (155/156)
Clinical Success
Pre-dilatation
89.8% (141/157)
Post-dilatation
39.1% (61/156)
Provisional Stent
LL cm:
LL > 25 cm:
40.4% (63/156)
33.3% (33/99)
52.6% (30/57) 10

11. How was this low Stent rate Without the Expense of Patency Possible?
3 minutes predilation with uncoated balloons followed by
3 minutes inflation with DCBs with sufficient overlap if more than one balloon was used
Another 5 minutes plain balloon inflation in case of suboptimal result after DCB using up to 30cm long balloons

12. Balloon (DCB) to Vessel Diameter Ratio
Tip No. 2
Balloon (DCB) to Vessel Diameter Ratio

13. A Post-Hoc Subgroup Analysis Suggests that Full Wall Apposition of Lutonix® (drug coated balloon percutaneous transluminal angioplasty) 035 Contributed to Increased Primary Patency Results at 12 Months*
The bar graph with average 0.9:1 is the average treated over stretch of DCB = 0.9± 0.2 (n=294) compared to the PTA average of 1.0 ±0.2 (n= 145)
LEVANT 2 Clinical Trial
Average 0.9:1
Balloon to Artery Ratio
LEVANT 2 Full Wall Apposition
Sub Group
≥1 .04: 1 Balloon to Artery Ratio
The bar graph ≥ 1.04 are those subjects In DCB (n=68) and PTA (n = 39) with treated over stretch ≥ 1.04
The mechanism of action of a drug coated balloon is to deliver the drug coating to the inner wall of the vessel while dilating the stenosed area. To do so, proper wall apposition Wall apposition of the balloon is needed to get a good contact of the balloon surface with the vessel wall undergoing treatment.
Therefore, it is important to achieve a minimum of 1:1 balloon-to-artery ratio of the treatment device. The protocol pre-specified a ratio value of (1:1) which is aligned with the mechanistic action of a drug coated balloon.
When analysing patency results in the study of the subgroup with a balloon-to-artery ratio of the LTX DCB device >1.04, the efficacy was statistically superior for the LTX DCB compared to the control PTA (almost 80% vs 48.2%, p= 0.001).
The treatment effect for this subgroup was 31.7% improved patency, as compared to the 12.6% for all patients in L2(ITT) which I just showed you in the previous slide.
It should be noted that the procedural analysis of the L2 ITT group showed that the DCB angioplasty procedure measured balloon to artery ratio was only 0.9 and did not achieve 1:1 balloon to vessel diameter ration.
(n=294)
(n=145)
(n=68)
(n=39)
A post-hoc subgroup analysis suggests the full wall apposition of the Lutonix® 035 Drug Coated Balloon (minimum 1.04:1 balloon-to-artery ratio of the treatment device) showed increased primary patency of 79.9% (at 12 months Kaplan Meier, not pre-specified). Primary patency is defined as absence of binary restenosis defined by DUS PSVR ≥2.5 and freedom from Target Lesion Revascularization (TLR). Primary safety by treatment balloon / artery ratio <1 was 85.8% (DCB) and 82.1% (PTA). Primary safety by treatment balloon / artery ratio >1 was 79.3% (DCB) and 75.5% (PTA). Warning: Do not exceed Rated Burst Pressure.

14. Differences in Key Procedural Variables between German and non-German cohorts of Levant 2
P-value
Transit Time per Balloon (seconds)
21.8 ± 11.9 (105)
39.5 ± 29.3 (327)
<0.001
Inflation Time per Balloon (seconds)
129.8 ± 74.3 (157)
167.4 ± 91.7 (455)
Max Pressure of Treatment Balloons (atm)
9.0 ± 2.2 (157)
7.7 ± 2.1 (455)
Provisional Bailout Stenting, % (n/N)
6.3% (8/126)
3.1% (11/350)
0.115
Maximum %DS Post Procedure
19.4 ± 10.4 (126)
21.5 ± 9.7 (349)
0.039
Minimum Lumen Diameter (MLD) post procedure
3.9 ± 0.8 (126)
3.8 ± 0.7 (349)
0.095
Procedure Duration, minutes
53.4 ± 20.9 (126)
58.7 ± 32.1 (350)
0.085
Procedural Success (Core Lab, All Lesions), % (n/N)
90.5% (114/126)
87.4% (305/349)
0.358 .
‡values are mean ± standard deviation (n evaluable) unless otherwise specified
 T-tests for means and X2-tests for proportions.

15. Levant 2: Kaplan-Meier Analysis of Primary Patency German Cohort
79.4%
57.8%

16. Levant 2: Kaplan-Meier Analysis of Freedom-from-TLR German Cohort
96.1%
82.0%

17. Levant 2-Subcohort Analysis German vs. Non-German Cohort

18. DEFINITIVE AR 12-Month Patency DAART RCT Patients
DAART Arm: Increased lumen gain may improve 12-month patency
Percent
Slide from SC A VIVA 2014 DAART Symposium and PA A .
N = N = 18
N = N = 16

19. Time to Balloon Inflation & is Predilatation Needed?
Tip No. 3
Time to Balloon Inflation
&
is Predilatation Needed?

20. Differences in Key Procedural Variables between German and non-German cohorts of Levant 2
P-value
Transit Time per Balloon (seconds)
21.8 ± 11.9 (105)
39.5 ± 29.3 (327)
<0.001
Inflation Time per Balloon (seconds)
129.8 ± 74.3 (157)
167.4 ± 91.7 (455)
Max Pressure of Treatment Balloons (atm)
9.0 ± 2.2 (157)
7.7 ± 2.1 (455)
Provisional Bailout Stenting, % (n/N)
6.3% (8/126)
3.1% (11/350)
0.115
Maximum %DS Post Procedure
19.4 ± 10.4 (126)
21.5 ± 9.7 (349)
0.039
Minimum Lumen Diameter (MLD) post procedure
3.9 ± 0.8 (126)
3.8 ± 0.7 (349)
0.095
Procedure Duration, minutes
53.4 ± 20.9 (126)
58.7 ± 32.1 (350)
0.085
Procedural Success (Core Lab, All Lesions), % (n/N)
90.5% (114/126)
87.4% (305/349)
0.358 .
‡values are mean ± standard deviation (n evaluable) unless otherwise specified
 T-tests for means and X2-tests for proportions.

21. DCB Technology Drug Release
Mechanism of action
DCB matrix coating:
Paclitaxel + Urea
During transit to lesion:
Majority of matrix protected within folds of the balloon
DCB inflation:
Matrix contacts blood
Blood hydrates urea
Urea releases paclitaxel
Due to its hydrophobic and lipophilic properties, paclitaxel binds to vessel wall
Previously approved DOC 1B
Mechanism of action is not through high pressure and pushing drug into tissue, but through a chemical transfer that occurs as the excipient, urea, hydrates and helps to expel paclitaxel from the balloon wall into tissue.
Given this mechanism of action, the engineers and designers had to make several decisions: which drug to use? At what dose? How should the balloon be coated? What excipient works best with which balloon material? A few of these decisions will be covered next.
Additional Detail:
During inflation, the coating on the IN.PACT Admiral DCB comes into contact with blood. Urea, the excipient in the coating, has a strong affinity for water; that is, it is hydrophilic. This characteristic facilitates the release of paclitaxel from the balloon, which essentially pushes the paclitaxel into the vessel wall.
Within the first 60 seconds of balloon inflation, a therapeutic dose of paclitaxel – 3.5 micrograms per millimeter squared – is delivered to the vessel wall. With its lipophilic properties, paclitaxel binds to the vessel wall. On a cellular level, its hydrophobic and lipophilic characteristics allow paclitaxel to enter the media and adventitia layers of the vessel, reaching smooth muscle cells – the cells most responsible for restenosis. Paclitaxel binds to and stabilizes the microtubules of the smooth muscle cells. This action prevents smooth muscle cell division and leads to apoptosis (cell death). This in turn minimizes cell proliferation and neointimal thickening, effectively maximizing the arterial lumen and “turning off” the process that leads to restenosis.

22. Is Predilatation Mandatory? Illuminate FIM

23. How to Avoid Geographical Miss
Tip No. 4
How to Avoid Geographical Miss

24. Limitation of DES placement in long BTK-Lesions
Baseline
Balloon-angioplasty
Residual stenosis
Focal stenting with DES
They performed spot-stenting with DES. The problem then can be, if treatment are is much longer than the stented are, that restenosis will occur proximal and distal to the stent. Therefore we think DES do only make sense if full lesion covereage is performed.
Follow-up

25. DCB and Minimizing Geographical Miss
1. PRE-DILATATION
Required for all lesions prior to DCB procedure
Size - Diameter: 1 mm less than RVD
Size - Length: should not be greater than planned DCB length
DRUG-COATED BALLOON
DCB diameter RVD = 1:1; length 1 cm beyond lesion on both ends
Inflation: Time ≥ 3 minutes; Pressure < RBP as required to reach full DCB expansion
Overlap multiple DCBs by at least 1cm
POST-DILATATION
If residual stenosis ≥ 50% or flow-limiting dissection
Standard or high pressure PTA balloon diameter 1:1 to RVD
Short/focal length as necessary to treat the extent of residual stenosis or dissection
Continuing on Angioplasty of lesions, slide to discuss use of Antiproliferative balloon technology and note to avoid geographic miss of lesion.
Slide approved in DOC 1B (slide 38)
Predilation is required for all lesions prior to DCB. Use an uncoated PTA balloon that is 1 mm smaller than the Reference Vessel Diameter (RVD). If the vessel is severely calcified, consider bebulking the vessel. Use a Drug-Coated Balloon that is the same diameter as the vessel. Ensure it extends beyond the lesion by 1 cm at both the proximal and distal ends. This is important so as to avoid geographic miss. It’s a good idea to mark the lesion prior to the DCB procedure to avoid geographic miss.
Multiple DCBs – overlap at least 1 cm
Inflate the Drug Coated-Balloon for 3 minutes. Studies have shown the inflation times of 3 minutes results in less dissections and better outcomes than inflation times of 30 seconds. Consider post dilatation in the instance of residual stenosis or flow limiting dissection. For persistent residual stenosis or flow limiting dissections, consider spot stenting, choosing the shortest length that is necessary to fully treat the residual stenosis or dissection.
PROVISIONAL SPOT STENTING
For persistent residual stenosis ≥ 50% or flow-limiting dissection
Minimum length as necessary to fully treat the residual stenosis or dissection

26. How to Avoid Geographical Miss
Treat from healthy segment to healthy segment, overlap at least 10mm
If more than one DCB is needed guarantee DCB overlap of at least 10mm
Use landmarks
Ruler
Overlay / roadmap function

27. Balloon Overlap DEBs Overlay

28. Balloon Overlap DEBs Ruler
Two overlapping IN.PACT Admiral DCB SFA (5/120 & 5/150mm)

29. Optimizing DCB Intervention Proposed Fem-pop treatment algorithm
Each femoro-popliteal lesion
Pre-Dilatation with 1:1 sized balloon
Flow-limit Dissection or
residual stenosis >50%?
Flow-limit Dissection or
residual stenosis >50%?
YES NO
Stent
YES
DEB NO
Atherectomy

30. Optimal PTA in the Era of DCB
Pre-dilatation practice when DCB is the primary treatment strategy:
Usage*
Sizing
Inflation parameters (pressure, duration)
Approach to DCB treatment:
Technique to minimize geographic miss (use of ruler / grease pencil?)
Sizing & inflation pressure / duration
Triggers for post-dilatation and/or provisional stents
Best 3 minute jokes
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* In the US, pre-dil is required prior to DCB per the Medtronic (and Bard) IFU