Michael Knizhnik — Endovascular treatment for patients with critical limb ischemia: yesterday, today and tomorrow

Michael Knizhnik
Belinson Hospital, Rabin MC, Petah-Tiqva, Israel
"
Almaty 4 July 2014

 66% of PAD patients may have stable symptoms. Up to 5% will eventually
require amputation.
 However, cardiovascular mortality in patients with PAD is sharply increased
with a significantly higher overall death rate. JVIR 2013
 A diagnosis of PAD is critical evidence of more atherothrombotic, with
high risksof subsequent CVS events and death. Cardiovasc Dis.2005

• Within 3 months of presentation:
 – death in 9%
 – MI in 1%
 – stroke in 1%
 – amputation in 12%
 – persistent CLI in 18%
• 1-year mortality: 21.0%
• 2-year mortality: 31.6%

interventional radiologist
vascular surgeon
orthopaedist
podiatrcardiologist
endocrinologist
?
plastic surgeon

Recommendation 24. Optimal treatment for
patients with critical limb ischemia (CLI)
Revascularization is the optimal
treatment for patients with CLI

Which kind of
revascularization?
F3.2 Endovascular treatment of infrapopliteal occlusive disease
Endovascular procedures below the popliteal artery are usually indicated for limb
salvage and there are no data comparing endovascular procedures to bypass
surgery for intermittent claudication in this region.
Angioplasty of a short anterior or posterior tibial artery stenosis may be performed
in conjunction with popliteal or femoral angioplasty. Use of this technique is usually
not indicated in patients with intermittent claudication.
There is increasing evidence to support a recommendation for angioplasty in
patients with CLI and infrapopliteal artery occlusion where in-line flow to the foot
can be re-established and where there is medical co-morbidity. In the case of
infrapopliteal angioplasty, technical success may approach 90% with resultant
clinical success of approximately 70% in some series of patients with CLI. Salvage
rates are reported as being slightly higher.

 Röntgen 1895 X-ray imaging
 Heuser 1919 Venography in man
 Moniz 1927 Arteriography
 Forssmann 1929 basilic vein cath. to the heart*
 Dos Santos 1929 tranlumbar aortography
 Farinas 1941 transfemoral aortography
 Seldinger 1951 arterial access
 Fogarty 1963 embolectomy catheter
 Dotter 1964 arterial dilation w rigid catheters
 Gruntzig 1974 balloon angioplasty
 Palmaz 1985 balloon expandable stent
 Parodi 1991 stent graft

S.Seldinger
1953 a method of percutaneous insertion of a
catheter into a blood vessel or space.
A needle is used to puncture the structure and a guide wire is threaded
through the needle; when the needle is withdrawn, a catheter is
threaded over the wire; the wire is then withdrawn, leaving the
catheter in place.

Ch. Dotter M. Judkins
Described angioplasty in 1964,
jugular veinthrough theliver biopsyalso developed

A. Gruentzig
1974 - Peripheral angioplasty

1984 the original nitinol stent, which was
the first in the world implanted into vessels,
biliary tracts, the esophagus, and other hollow organs.
I.Rabkin

Foot arteries anatomy & angiosomes
•IN NORMAL SUBJECTS, FOOT CIRCULATION IS ANASTOMOTIC
LOTS OF ARTERIAL-ARTERIAL BRANCHES = COLLATERALS
In Diabetic Patients Collaterals Formation is Reduced or Absent
Circulation, 1999;99:2239-2242;
Cardiovasc Res. 2001 Feb 16;49(3):554-60;
Circulation, 2004;2343-2348
IN DIABETIC SUBJECTS, FOOT CIRCULATION BECOMES
BECAUSE OF LACK OF COLLATERALSFUNCTIONALLY TERMINAL
THIS IS THE REASON WHY WE NEED TO IMPROVE THE
FLOW TO THE WOUNDED AREAMOST DIRECT
THE SAME REASON WHY WE NEED TO LOOK AT THE WOUND,STUDY THE VASCULAR ANATOMICAL
SITUATION, IDENTIFY THE RELATED ARTERY AND TREAT IT WHEN POSSIBLE

Angiosome:
Anterior Tibial
Angiosome:
Peroneal Calcanear Branch
Angiosome:
Posterior Tibial
M. Manzi, MD

Contralateral femoral (retrograde)
Ipsilateral femoral (antegrade)
Ipsilateral popliteal (retrograde)
Pedal

HEALING VARIABLES
•Number of vasc. levels involved
•Plantar arch patency
•Amount of tissue destruction
•Presence of infection
•Need of debridement or skin
graft
•Available conduit for bypass
•Comorbidity
•Nutritional status

• Complete vessel treatment
- pressure wire
• Restenosis less of an issue
• Clinical follow-up and team
approach more important
- wound clinic

01-2014 JB5799
In high risk patients, choosing Visipaque can help optimise
outcomes and minimise costs6,12
Visipaque reduces the likelihood of cardiac and renal
complications in high risk patients6-10
Visipaque helps minimise discomfort for patients undergoing
intra-arterial procedures11
In patients at high risk of contrast-related adverse events,
choice of contrast agent is critical1-4
Visipaque is the only X-ray contrast agent for intravascular use
with an osmolality similar to blood at all iodine concentrations5

01-2014 JB5799
In patients at high risk of contrast-related
adverse events, choice of contrast agent is
critical.

01-2014 JB5799
An increasing number of patients are at high risk of
contrast-related adverse events
Increased
risk of13
Cardio-renal
syndrome15-17
Increased
risk of14
e.g. with diabetes, renal
impairment, proteinuria,
hypertension, gout, recent
nephrotoxic treatment1,2
CM volume and
osmolality should
be limited2
Risk factors for CM-related adverse events1,2,13-17
Ageing
patients
CVD
CKD
Intra-
arterial
procedures
Other
vulnerable
adult patients
Paediatric
patients
There are many interacting risk factors for CM-related adverse events, including
age, CKD, CVD and interventional cardiology procedures1,2,13-17
– As the population ages, the number of patients at high risk of CM-related adverse
events increases
CKD: chronic kidney disease
CM: contrast media
CVD: cardiovascular disease

01-2014 JB5799
Patients with multiple risk factors are more likely to experience
adverse events such as contrast-induced acute kidney injury18
CKD is the most significant risk factor for CI-AKI, which is the 3rd most common
cause of hospital-acquired acute renal failure19
Formal risk scoring in the cardiac angiography setting shows that the presence
of multiple risk factors increases the likelihood of CI-AKI further18
* SCr >1.5 mg/dl score =4 or eGFR score =2 (40–60 ml/min/1.73 m2), 4 (20–40 ml/min/1.73 m2), or 6 (<20 ml/min/1.73 m2)
† SBP <80 mmHg ** NYHA class III/IV± pulmonary oedema †† baseline haematocrit <39% for men and <36% for women
CI-AKI risk increases as the number of risk factors increases
(n=8,357)18
Renal impairment* 2–6
Hypotension† 5
Intra-aortic balloon pump 5
Congestive heart failure** 5
Age >75 years 4
Anaemia††
3
Diabetes mellitus 3
CM volume 1 per 100
ml3
Risk factors Score
≤5
6-10
11-15
≥16
7.5%
14.0%
26.1%
57.3%
Total score Risk levelIncidence of CI-
AKI
Low
Moderate
Hig
h
Very
high
Adapted from Mehran 200418
CM: contrast media
CI-AKI: contrast-induced acute kidney injury
eGFR: estimated glomerular filtration rate
NYHA: New York Heart Association
SBP: systolic blood pressure
SCr: serum creatinine

01-2014 JB5799
In patients undergoing interventional procedures, contrast-induced
acute kidney injury increases the risk of further cardiovascular
events20,21
Cardio-renal syndrome can be exacerbated by CI-AKI, which increases the risk of death, CV events
and associated hospital stays in patients undergoing percutaneous coronary intervention20-25
CM: contrast media
CV: cardiovascular
MACE: major adverse cardiac events
PCI: percutaneous coronary intervention
%patients
16
12
8
4
0
13.8%
Outcome: Mortality In-hospital MACE In-hospital stroke Vascular complications
Adapted from Iakovou 200220
Cardiovascularevents
No CI-AKI
CI-AKI
p<0.0001
5.3%
p=0.001
7.9%2.9%4.7%1.4%
p=0.0008
4.7%0.9%
p=0.0003
CI-AKI increases the risk of CV events in patients receiving CM for PCI (n=8,268)20

01-2014 JB5799
Even transient contrast-induced acute kidney injury results in increased
hospitalisation, morbidity and mortality for cardiovascular events
Both transient and persistent CI-AKI
are prognostically significant for
hospitalisation, morbidity and mortality
during extended follow-up26,27
Physicians may disregard mild or transient
increases in SCr after CM procedures,
even though they lead to worse short-
and long-term outcomes26
* CI-AKI defined as a >25% increase or >0.5 mg/dl (>44.2 mmol/l) increase in SCr within two days of intravascular administration
of iodinated CM when no other major kidney insult was identiﬁed
CI-AKI* increases the risk of hospital admission for CV events
(incuding myocardial infarction, heart failure, stroke and target
vessel revascularisation) dialysis and death26
Cumulativeeventrateforcompositeendpoint
012
24
36
0.6
0.4
0.2
0.0
Follow-up (months)
Persistent CI-AKI
Transient CI-AKI
No CI-AKI
p=0.021
p=0.035
Hospitaladmission,dialysisanddeath
Adapted from Wi 201126
CM: contrast media
CV: cardiovascular

01-2014 JB5799
Patients at higher risk of contrast-induced acute kidney injury are more
likely to incur the considerable long-term costs associated with it
When adjusted by risk level, the average cost of managing CI-AKI per PCI
performed is higher in high risk patients, since they are more likely to develop it28
– The largest cost driver is the increased length of stay associated with the
initial hospitalisation28
*Risk levels taken from the risk scoring system developed by Mehran et al (2004)18
Average 1-year cost per CI-AKI event28Average 1-year cost per PCI procedure28
12,000
8,000
4,000
0
Cost$
Cost$
Patient CI-AKI risk level*
CI-AKI eventLo
w
Hig
h
Very
high
Moderat
e
Dialysis
MACE
In-hospital
Adapted from Subramanian 200728
PCI: percutaneous coronary intervention
9,000
6,000
3,000
0

01-2014 JB5799
Choice of contrast agent is critical to minimise the
likelihood of contrast-related events in high risk patients1-4
Hyperosmolality has long been recognised by international guidelines as one of the key
determinants of CM-related adverse events, particularly in high risk patients1-4
ACR: American College of Radiology
CM: contrast media
CV: cardiovascular
KDIGO: Kidney Disease Improving Global Outcomes
Increased
risk of6
Increased
risk of2,3
Increased
risk of29
CV
effects
and
MACE
Patient
discomfort
Hyperosmolality as a factor in CM-related adverse events1-3,6
CI-AKI
The KDIGO Clinical Practice Guideline states that
wherever possible isosmolar agents should be used
in people with CKD at high risk for CI-AKI4
ACR guidelines suggest that for intra-arterial injections,
isosmolar CM are associated with the least amount
of discomfort2
2013
2013
ACR guidelines state attention should be paid to
limiting osmolality in patients with CV disease2
2013
Hyper-
osmolality

01-2014 JB5799
Visipaque is the only X-ray contrast agent for
intravascular use with an osmolality similar to
blood at all iodine concentrations5
Visipaque reduces the likelihood of contrast-related
cardiac and renal complications in high risk patients6-10
Visipaque helps minimise discomfort for patients
undergoing intra-arterial procedures11

01-2014 JB5799
Examining the rate of contrast-induced acute kidney injury with
Visipaque compared with low osmolar agents in high risk patients
A recent comprehensive meta-analysis investigated the incidence
of CI-AKI in comparative studies of isosmolar Visipaque and LOCM6
A broad range of publications were considered6
The baseline SCr across all included studies was ≥1.6 mg/dl and
average
GFR was ≤50 ml/min/1.73 m2, indicating that patients had, on
average, moderately impaired renal function6
GFR: glomerular filtration rate
LOCM: low osmolar contrast media
-Strict inclusion criteria were applied6
- studies needed to be randomised, prospective,
head-to-head comparisons of Visipaque and a LOCM
- they needed to have CI-AKI as a primary and/or
secondary endpoint
- they needed to be of high methodological quality
(with a Jadad score ≥2)25
were included
in the meta-analysis
145
potential articles
were identified

01-2014 JB5799
Visipaque is associated with a lower risk of contrast-induced acute
kidney injury than low osmolar agents in high risk patients6
Intra-arterial use of isosmolar Visipaque significantly reduced the risk of CI-AKI*
compared to LOCM† in the interventional cardiology setting (RR=0.46; CI: 0.27–0.79;
p=0.004)6
*CI-AKI defined as SCr increase of ≥0.5 mg/dl from baseline measured up to 3 days after contrast media exposure
†Pool of LOCM (iohexol, iomeprol, iopamidol, iopromide, ioversol and ioxaglate)
CI-AKI risk is lower with intra-arterial Visipaque than with LOCM (n=4,769)6
0.01 0.1 101
Study
100
Aspelin (NEPHRIC) 03
Hill 94
Sinha 04
Wessely 09
Hardiek 08
Laskey 09
Solomon (CARE) 07
Juergens 09
Li 08
Nie 08
Han 10
Hernández 08
Rudnick (VALOR) 08
Jo (RECOVER) 06
Mehran (ICON) 09
Favours Visipaque Favours LOCM
Adapted from McCullough 20116
CI: confidence interval
RR: relative risk

01-2014 JB5799
Visipaque has minimal cardiovascular effects, which is critical when
managing patients at risk of contrast-related adverse events
Fluid shift as CM flows through coronary arteries may lead to adverse CV effects,
resulting in heightened cardiac risk31
Potential CV effects of CM Benefits of Visipaque
Changes in electrophysiological parameters
(e.g. QT-interval, QRS vector difference)32-35
Less impact on electrophysiological parameters than
ioxaglate and iohexol32-35
Haemodynamic changes can induce
myocardial ischaemia during coronary
procedures35,36
Minimal change in left ventricular systolic pressure
(compared to a significant fall with iopromide)35
Minimal changes in haemodynamic parameters
(left ventricular end diastolic pressure, aortic pressure)
compared with iohexol36
Reduced contractility and lowered cardiac
output, resulting in the heart beating faster
in order to compensate35
Lower impact on heart rate variability than
iopromide, ioxaglate or iomeprol in clinical trials35,37-39
Electrical
activity
Mechanical
performance
Heart rate
variability
CM: contrast media
CV: cardiovascular

01-2014 JB5799
Visipaque is associated with fewer major adverse cardiac events
than low osmolar agents in the interventional cardiology setting8-10
Visipaque was associated with fewer MACE than LOCM in the interventional cardiology setting8-10
Several large prospective clinical trials have shown that Visipaque is associated with significantly
fewer MACE (such as cardiac death, stroke and coronary artery bypass graft) than LOCM8-10
*In-hospital included cardiac death, emergency recatheterisation for ischaemia, repeat revascularisation, CABG, subacute thrombosis,
stroke/TIA, non-fatal MI, abrupt closure of target vessel, systemic arterial thromboembolic event, and unplanned coronary artery bypass
surgery
%patients
MACE criteria*
p<0.025
In-hospital8
(n=1,276)
In-hospital9
(n=856)
≤30 days post-discharge10
(n=208)
p=0.003
p=0.027
iopamidol ioxaglate iopromideVisipaqu
e
Visipaqu
e
Visipaqu
e
1.9%5.4%4.8% 8.8%9.5%9.0%
12
10
8
6
4
2
0
Majoradversecardiacevents
Adapted from Harrison 20048, Davidson 20009 and Nie 200810
CABG: coronary artery bypass graft
MI: myocardial infarction
TIA: transient ischaemic attack

01-2014 JB5799
In high risk patients, choosing Visipaque can help
optimise outcomes and minimise costs6,12

•Major amputation was required more often in those with fewer patent arteries (P <
0.001).
When is a technically successful peripheral angioplasty effective
in preventing above-the-ankle amputation
in diabetic patients with critical limb ischaemia?
Faglia E et all. Diabetic Medicine 2007; 24: 823-829
Crural patent arteries after PTA N. patients no requiring
amputation (n=398)
N. patients requiring
amputation (n=22)
3
2
1
0
67
143
179
9
0
0
7 (4%)
15 (62%)

• 159 TMA/153 patients
• 159 limbs revascularized: bypass (15.2%) and by endovascular procedure (84.8%).
• Predictive factors for healing: - number of vessels open at ankle level (OR: 7.42)
Effect of revascularization on transmetatarsal amputation healing
in diabetic ischemic foot
Dalla Paola et al. VII meeting of the DFSG, 2008
N. open vessels Time of healing (days)
0 160.0 ± 155.6
1 125.9 ± 113.7
2 95.0 ± 79.5
3 88.6 ± 108.5
By-pass =78+/-52 days
p=0,0
4
p=0.03
n.s.s.
“In diabetic ischaemic foot TMA outcome is influenced to kind of
revascularization. Every vessel open at ankle level reduces about of 31 days the
time of healing. Data from this study indicate that efforts should be done
during revascularization to open the most number of vessels to reduce time of
healing.”

BTK PTA…Yesterday
 For limb salvage
only;
 At least one direct
vessel to the foot
(ankle level);
 For wounds healing
too;
 For deambulation
salvage;
 Two or three vessels to
the foot (inflow);
 Foot vessels
revascularization
(outflow).
BTK PTA… TODAY

 ≠ Treating angiographic images
 = Treating patients’ complaints
 Restoring outflow
 1 artery straight-line flow to foot
= PRIMARY GOAL OF ANY
TREATMENT
EXC : Diabetics poor
collateralisation
PRE POST

 Single spot lesions
 A rare example
Pre-op Post-op

 Occlusion all
3 BTK vessels
 Which vessel
to treat?
Pre-op Post-opPre-op (distal)

 Occlusion at distal popliteal: which vessel to treat?
Pre-op Post-opPre-op Post-op

 Length dependent strategy
decision
 Short lesion
 Focal PTA technique
+ Balloon expandable stents
+ Nitinol stents
 Intermediate lesion
 Nitinol stents
 Long lesion
 Long low pressure balloons
with or without additional
focal stenting

 Lesion passage
 Stiff 0.014 – 0.018”
hydrophilic wire
 Extra support with
4-5F multipurpose
glide cath

 Tandem lesion on ATA
Pre Post

Pre-op Post-op
 Distal lesion

Stabilizer+
Cordis 0.014”
Ultrasoft SV
BSCI 2x30
 Ultrasoft SV (BSCI) – short occlusion distal ATA

 After suboptimal PTA
 Flow-limiting dissection
 Residual stenosis
 Coronary stents
 Dedicated BTK stents
 Bare
 Passive coating
 Active coating
 Bioabsorbable

 Pro-kinetic Explorer (Biotronik)
PRE POST PRE

Cypher (Cordis) – Distal P3-segment high grade stenosis
3.0/28
Cypher stent
Pre-op

 Cypher (Cordis) – proximal lesion
Pre-op
3.5/33
Cypher
stent
Guidewire
passage
and PTA
Post-op
PTA

 Cypher (Cordis) – Occlusion TFT
Pre-op
Post-op
2x Cypher stent

Magic Explorer (Biotronik) – Bifurcation lesion
Pre Post

 Disadvantages
 Crushability
 Limited flexibility
 Stent damage
 Disturbed flow dynamics

 Dedicated design for small vessels
 Do not place a large vessel stent in smaller diameters!
 Metal overload
 Impaired flow dynamics


 Dilation
popliteal lesion
 Passeo baloon
 3x80
Courtesy of O. D’Archambeau – J Hendriks


 Dilatation
ATA lesion
 baloon3x20
 Resulting in
dissection


 Stenting
 4x80


 Post dilation
 3x80

PRE POST
Knee straight
POS
Knee be

 Low pressure balloons
 L 8-17 cm
 Ø2.5-3.5mm
 Improve outcome with
spot stenting
 Achieving dynamic flow
into foot is goal

DilationPre-op Post-op
Passeo-18 (Biotronik)
Diffusely diseased PTA

Pre-op Post-op
Revascularization existing feeding collateral

 Additional focal stenting on areas of low success
pre-op
Dissection
after PTA
Multi-link
Vision
post-op


Dilation ATA
2.5x170
2 times
Resulting in distal flow
limiting dissection

Why and when endoluminal
atherectomy? M.Manzi, 2009
•Young patients
•Popliteal tract
•SFA intrastent reocclusion
In order to avoid stent !
• BTK high risk for PTA segments
(bi-trifurcations)
•PTA restenosis
•Light calcified distal plaques
Alternative
to balloon
PTA

ischemic rest pain, ulcers orChronic
gangrene attributable to objectively
proven arterial occlusive disease
and is tochronicityThe term CLI implies
be distinguished from acute limb
ischemia
Ankle pressure
< 50 mm Hg
Toe pressure
< 30 mm Hg
TcpO2
< 30 mm Hg
Norgren et al. TASC II, Eur J Vasc Endovasc Surg 33, 2007

diabetes
neuropathy
trauma,
deformity
ulcer
lack of healing
infection
gangrene
1 millionone mil. major amputations ww p/y
54% mortality, 46% amputation at 1y for untreated CLI
•www.iwgdf.org-International Working Group of Diabetic Foot
•Lepäntalo et al: EJVES 1996;11 (2): 153-157

Revascularization + extra-Vascular care
Rogers LC, Armstrong DL: Podiatry Care, Chapter 113, Rutherford's Vascular Surgery, 7th
Edition, Cronenwett JL, Johnston KW, editors, Elsevier Inc, 2010
• Healing and Perfusion: non linear
correlation
• Probability of healing:
– Suboptimal with suboptimal
perfusion
– Maximized with optimal wound care
and perfusion
– Best preserved in presence of optimal
and durable perfusion

• Makes healing faster and better
O.Iida et al. angiographic restenosis and its clinical impact after infrapopliteal
angioplasty. Europ J of Vasc and Endovasc Surgery 2012

Reiber, et al. Diabetes Care, Vol 22, Number 1, January 1999
External Triggers of Ulceration

.1Durable perfusion is an insurance policy against the casual
occurrence of new ulcers
.2Scarce Perfusion makes foot vulnerable to recrudescence
and recurrencies
optimal Perfusion: F.Vermassen 2010
sub-optimal Perfusion:

Frequency and magnitude of reinterventions in CLI have a
known bad implication on patient’s survival and QoL [1]
.1Conte M.S Suggested objective performance goals and clinical trial design for evaluating catheter-
based treatment of critical limb ischemia. JVS 2009;50:1462-1473
Ouriel K, Lancet 2001, data of ‘60

Limb Salvage correlates poorly with Primary Patency, less
poorly with Secondary Patency
•Primary Patency reduces TLR, adds life and QoL to CLI
Patients
T.Kudo et al. The effectiveness of percutaneous transluminal angioplasty for the treatment of
critical limb ischemia: A 10-year experience. J Vasc Surg 2005;41:423-35.)

Patency clinically relevant when WRA is involved [1-2]
.1Neville et al. Revascularization of a Specific Angiosome for Limb Salvage: Does the Target Artery Matter? Ann Vasc Surg 2009; 23: 367-373
.2Iida O. et al. Importance of the Angiosome Concept for Endovascular Therapy in Patients with Critical Limb Ischemia - Catheterization and
Cardiovascular Interventions 75:830–836 (2010)
[1] [2]

M.Manzi et al. 2009
• Improved functional outcome
following re-establishment of the
plantar arch due to suboptimal
results of tibial revascularization
135 of 1331 CLI patients treated at Abano Terme Clinic (Italy) from 2007 to 2008) by pedal-
plantar-loop technique due to sub-optimal ATA revascularization and/or risk of amputation

 Below-the-ankle run-off reduce MALE [1]
O.Iida et al. Anatomical Predictors of Major Adverse Limb Events after Infrapopliteal Angioplasty for Patients with Critical Limb
Ischaemia due to Pure Isolated Infrapopliteal Lesions. European Journal of Vascular and Endovascular Surgery44 (2012) 318e324

Microcirculation to the wound related territory increase limb
salvage
Utsunomiya M et al. Impact of wound blush as an angiographic end point of endovascular therapy for patients with critical limb
ischemia. J Vasc Surg 2012;55:113-21

 Patency necessary but not sufficient for functional
limb preservation (extravascular care = key therapy
component)
 Restenosis becomes clinically relevant
 when involves the wound related artery
 when occurs during the healing process
 as new ulceration occur within the target angiosome,
triggered by external factors
 Prolonged better than short-term, Primary Patency
better than Secondary Patency

Technically best fitting the extensive, multivessel, long diffuse
BTK disease of real world CLI Patients
• 74% of all lesions in BTK
• 66% occlusions
• 50% occlusions >10 cm
• Tissue loss associated with significant
worse, BTK concentrated disease[2-3]
• Arterial Disease extension and distribution in CLI and Diabetes [1]
.1Graziani L et al. Vascular Involvement in Diabetic Subjects with Ischemic
Foot Ulcer: a New Morphologic Categorization of Disease Severity Eur J
Vasc Endovasc Surg 33, 453 460 (2007)
.2Diehm N et al. Association of Cardiovascular Risk Factors with Pattern of
Lower Limb Atherosclerosis in 2659 Patients Undergoing Angioplasty. Eur J
Vasc Endovasc Surg 31, 59–63 (2006)
.3A.Bradbury et al. Bypass versus Angioplasty in Severe Ischaemia of the
Leg (BASIL) trial: A description of the severity and extent of disease using
the Bollinger angiogram scoring method and the TransAtlantic Inter-Society
Consensus II classification JVS 2010

.1D.Scheinert, J Am Coll Cardiol 2012;60:2290–5)
.2H.K.Soder, J Vasc Interv Radiol 2000; 11:1021–1031
.3F. Baumann, J Vasc Interv Radiol 2011; 22:1665–1673
.4F.Fanelli, J Endovasc Ther. 2012;19:571–580
.5F.Liistro, TCT 2012 oral presentation
.6A.Schmidt, Catheter Cardiovasc Interv. 2010 Dec 1;76(7):1047-54
101 Patients
12m Angio
PTA arm PTA arm
60 Patients
10m Angio
33 Patients
6m Angio
11 Patients
12m Angio
67 Patients
12m Angio
58 Patients
3m Angio
PTA arm
A.Schmidt LINC 2013

• Single Center Registry
• IN.PACT Amphirion
• Long BTK lesions > 80
cm
• 104 Patients
• Primary Endpoint: 3-
month binary
Restenosis rate
A.Schmidt JACC 2011
First DEB-BTK Experience
in complex, real world BTK
lesions

IN.PACT
(angio subgroup)
# patients / limbs 74 / 79
Male gender 51 (68.9%)
mean age (y) 73.5 ± 9.3
diabetics 54 (73%)
Renal insuff. 34 (45.9%)
RC 3 16 (20.3%)
RC 4 14 (17.7%)
RC 5 49 (62%)
RC 6 0 (0%)
avg lesion length 173±87 mm
Tot occlusions 61.9%
IN.PACT
(angio subgroup)
3m Ang. FU
Restenosis (>50%) 27.4%
Full-segm. Resten. 10%
Restenosis Length 64 mm
12m Clinical
FU
Deaths 16.3%
Limb Salvage 95.6%
Clinical Improv. (1)
91.2% (2)
Compl. wound heal. 74.2%
TLR 17.3%
(1) clinical improvement = reduction in size and/or depth of ulceration or improvement of rest-pain

IN.PACT
(angio subgroup)
PTA*
(histor. group)
3m Angiographic FU
Restenosis (>50%) 27.4% 69%
Full-segm. Resten. 10% 56%
Restenosis Length 64 mm 155 mm
Clinical FU
12-month 15-month
Deaths 16.3% 10.5%
Limb Salvage 95.6% 100%
Clinical Improv. (1)
91.2% 76.5%
Compl. wound heal. 74.2% 78.6%
TLR 17.3% 50%
(1) clinical improvement = reduction in size and/or depth of ulceration or improvement of rest-pain
vs historical PTA cohort (A.Schmidt et al. CCI 2010)
IN.PACT
(angio subgroup)
PTA*
(histor. group)
# patients / limbs 74 / 79 58 / 62
Male gender 51 (68.9%) 38 (65.5%)
mean age (y) 73.5 ± 9.3 70.5 ± 8.08
diabetics 54 (73%) 52 (89.7%)
Renal insuff. 34 (45.9%) 30 (51.7%)
RC 3 16 (20.3%) 0 (0%)
RC 4 14 (17.7%) 16 (25.8%)
RC 5 49 (62%) 46 (74.2%)
RC 6 0 (0%) 0 (0%)
avg lesion length 173±87 mm 183±75 mm
Tot occlusions 61.9% 64.9%

 Compared to matched historical PTA cohorts, IN.PACT DEB
shows a remarkable (>60%) decrease in angiographic restenosis
at 3-month and TLR-rate at 12-15 months (65%) in the treatment
of long / complex BTK lesions
 IN.PACT restenosis pattern presents more frequently focal

 Single Center Randomized (1:1)
 CLI, Diabetic patients
 IN.PACT Amphirion vs. std PTA
 Primary Endpoint: 12-month (>50%)
Angiographic RR
F.Liistro LINC 2013
CLI + Diabetes
150 (Tibial) Lesions
DEB
(75 lesions)
Std PTA
(75 lesions)
12m Angio / Clinical FU
Aspirin + Clopidogrel (1 month)
24 m Duplex / Clinical FU
random
(1:1)
First Randomized trial to assess
DEB vs. PTA in a complex CLI–
Diabetic population with 12-
month angiographic endpoint

DEB PTA p
Patients Nr 65 67
Mean age 74±9.4 y 75±9.6 y 0.7
Male gender 54 (83.1%) 52 (77.6%) 0.5
Diabetes 65 (100%) 67 (100%) 1
Hypertension 46 (70.8%) 52 (77.6%) 0.4
Smoking 13 (20.0%) 7 (10.4%) 0.1
Hypercholesterol. 23 (35.4%) 16 (23.9%) 0.1
Prev. PAD diagnosis 25 (38.4%) 23 (34.3%) 0.4
Serum creatinine 2.18±0.25 2.25±0.25 0.9
Dialysis 7 (10.8%) 7 (10.4%) 1
Obesity 23 (35.3%) 26 (38.8%) 0.5
Cor. Artery Disease 12 (18.5%) 10 (14.9%) 0.6
Cerebrov. disease 5 (7.7%) 7 (10.4%) 0.7
Limbs Nr 71 72 0.9
ABI 0.31±0.8 0.29±1.0 0.6
Concom. Fempop PTA 32 (49.2%) 35 (52.2%) 0.8
DEB PTA p
Lesions Nr 80 78
Tot Occlusions 62 (77.5%) 64 (82.1%) 0.5
Mean Length (mm±SD) 128±83 130±79 0.9
Severe Calcification 20 (25.0%) 22 (28.2%) 0.5
RVD (mm) 2.91±0.27 2.87±0.29 0.7
MLD (mm) 0.06±0.14 0.05±0.14 0.6
DS(%±SD) 97.2±7.7% 97.1±8.0% 0.9
DEB PTA p
IC 1 (1.4%) 3 (4.2%) 0.5
IIC 3 (4.2%) 5 (6.9%)
ID 7 (9.9%) 9 (12.5%)
IID 34 (47.9%) 32 (44.4%)
IIID 26 (36.6%) 23 (31.9%)
Texas Wound Class

DEB PTA p
Lesions Nr 80 78
pre-Dilatation 80 (100.0%) -
Subintimal Recanalization 17 (21.3%) 17 (21.8%) 0.8
Antegrade Recanalization 78 (97.5%) 75 (96.2%) 0.7
Retrograde Recanalization 2 (2.5%) 3 (3.8%) 0.7
Balloon Inflation Time (sec±SD)
142±38 140±50
0.5
Balloon Diameter (mm±SD)
2.90±0.39 2.85±0.36
0.4
Mean Balloon length (mm±SD)
148±83
140±79 0.5
Bailout Stenting 1 (1.3%) 1 (1.3%) 0.9
Technical Success [1] 80 (100%) 78 (100%) 1
Procedural Success [2] 65 (100%) 67 (100%) 1
.1Achievement of <30% residual stenosis by visual estimate
.2Achievement of Technical Success without procedural complications

DEB PTA p
Nr assessed Lesions 74 (92.5%) 74 (94.9%)
Lesion Assessment: ANGIO 67 (90.5%) 68 (91.9%) 0.8
DUPLEX 7 (10.0%) 6 (8.1%) 0.8
Restenosis (>50%) 20 (27.0%) 55 (74.3%) <0.001
Occlusion 13 (17.6%) 41 (55.4%) <0.001
Occlusion length (mm) 87±88 128±75 <0.001
12-month occl./baseline occl. %±SD 52±40 87±88 <0.001
Death 5(7.7%) 3(4.5%) 0.4
Major Amputation 0(0.0%) 1 (1.5%) 0.9
CVA 2 (3.1%) 3 (4.5%) 0.9
AMI 3 (4.6%) 3 (4.5%) 0.9
PCI 4 (6.2%) 3 (4.5%) 0.7
CLI recurrency 20(30.8%) 30(44.8%) 0.1
TLR 12 (18.5%) 29 (43.3%) 0.003
Non TLR 16 (24.6%) 23 (34.3%) 0.2
Cumulative MAE 19 (29.2%) 31 (46.3%) 0.05

Restenosis and Occlusion Rates TLR
Complete Wound Healing
12-month TLR
DEB vs. PTA:
18.5% vs. 43.3%
(p=0.003)
Major Adverse Events

.1F.Fanelli et al. J Endovasc Ther 2012;19:571–580
.2A.Cioppa – EuroPCR 2012
.3F.Liistro – TCT 2012
.4K.Suzuki – LINC Asia Pacific 2012
.5A.Schmidt et al. J Am Coll Cardiol 2011;58:1105–9 2011
10 Patients
12m Angio
75 Patients
12m Angio
65 Patients
12m Angio
20 Patients
4m Angio
74 Patients
3m Angio
A.Schmidt LINC 2013

 Sustained Primary Patency should be the goal of
modern revascularization therapies for CLI
 Balloon-based technologies remain the most versatile
solution to address the extent and burden of BTK
arterial disease in CLI
 IN.PACT DEB clinical evidence in complex, long BTK
lesions shows significantly lower restenosis rate and
burden, reduced TLR and improved wound healing vs.
PTA

Patient #1
 M, 32y/o,
 17 y with DM type 1,
 s/p kidney transplantation,
 necrotic wound on the lt.
foot
PRE

F, 81 y.o.
 DM, type 2, 34 y.
 HTN, IHD
 Rest pain
 necrotic wound on the
lt. foot
Lt TFA antegrade admittance

0-3 m
(89 patients)
0-6 m
(90 patients)
0-12 m
(92 patients)
Death
Amputation
TLR
1 (1.1%)
0%
1 (1.1%)
1 (1.1%)
0%
4 (4.5%)
2 (2.2%)
0%
8 (8.7%)
12M Survival from TLR, Occlusion, >50% Restenosis
83.7% Primary Patency
(PSVR < 2.5)
PSVR ± SD
3,1
1,1 1,1 1,1 1,2
0
0,5
1
1,5
2
2,5
3
3,5
4
4,5
5
baseline discharge 3m 6m 12m
P < 0.0001
P = NS
Micari et al. Euro-PCR 2011 Micari et al. JACC Cardiovasc Intervent 2012

Sample case of restenosis following DEB
administration
•CTO with significant calcium
burden
•Efforts were made to avoid
bail-out stenting, despite sub-
optimal acute results
•Further progression at
later time points,
especially around
calcified segment
Angiograms Courtesy of Gunnar Tepe, MD

Background of Atherectomy
…Problem = recoil/ restenosis
…Problem = dissection
…Problem = vessel stretch
causes injury
…Problem = Intima Hyperplasia
usually after 3 - 9 months in
the SFA
…Problem = relative
contraindication in vessel
segments with high external
forces (knee)
…no dilatation - avoids
barotrauma and recoil
…smoothens the lumen
…reduces the need of stents
Angioplasty
contemporarily
shifts the plaque…
Stenting
permanently shifts
…the plaque
DCA removes the
plaque…

Zeller et al. JACC 2006;48:1573-1578
Krankenberg et al. Circulation 2007
84
61
68
0
10
20
30
40
50
60
70
80
90
1-yr patency
Silverhawk
POBA
stent
[%]
De novo lesions, 4.5mm length

PHOTOPAC:
Laseratherectomy & DCB
vs. DCB in instent-
restenosis
PIs: Scheinert / Zeller
DEFINITIVE AR: DCA &
DCB vs. DCB in native
vessels
PIs: Tepe / Zeller

Entire cohort PTA DCB P
Primary patency @ 12 months [n/%/] 48/86 (55) 27/62 (43) 21/24 (88) <0.001*
TLR @ 12 months [n/%] 31/86 (36%) 29/62
(47%)
2/24 (8%) 0.001*
Restenosis@ 12 months [n/%] 39/86 (45%) 36/62
(58%)
3/24
(13%)
<0.001*
Secondary patency @ 12 months [n/%] 61/86 (71%) 39/62
(63%)
22/24
(92%)
0.015*
*: p<0.05; TLR: Target Lesion Revascularisation;
Sixt et al. JVS under revision

1. Hydrolyser
2. Oasis™ Thrombectomy System
3. Angiojet®
4. Amplatz Clot Buster (ATD)™
5. Trerotola Device
6. PMT™ Device

Mechanical Thrombectomy Local Thrombosis
Straub-Rotarex (8F)

Micro Catheter
0.014” Guidewire
Dilatable Tip
FDA Cleared
CE approved

The Intraluminal Approach
The size and unique design of the Voletek™ peripheral
crossing system enables it to cross
in micro-channels

57y white male; 45mm total occlusion >9 months;
CiTop™ succeeded after standard GW failed; followed by x1 stent.
Crossing time: 3 min
Occlusion
of the Rt.
popliteal
FIM Peripheral Randomized Study
Operator: Dr. Alexander Belenky

Endovascular Intervention offers a low risk
1-st choice therapy.
Surgery should be reserved for
– Diffuse severe vascular Calcification
– Failed endovascular intervention with
freq. restenosis
– Extensive gangrene with very prolonged healing

Michael Knizhnik — Endovascular treatment for patients with critical limb ischemia: yesterday, today and tomorrow

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