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New Technologies to Treat Critical Limb
Ischemia- (DES, DEB and Beyond)
Faisal Latif MD, FSCAI, FACC
Director Cardiac Catheterization Lab, VAMC
Assistant Professor of Medicine
Associate Program Director
Cardiology Fellowship Program
University of Oklahoma


I have No Financial Disclosure


Learning Objectives
• Enumerate drug-eluting options for CLI
• Discuss data on Drug-Eluting options in CLI
• Study Impact of therapies on Amputation


Surgery vs. PTA
• 452 patients with severe limb
ischemia (25% true CLI)
suitable for both surgery and
PTA
• Randomized to Surgery-first
(n=228) vs PTA-first (n=224)
• Primary endpoint: Amputationfree survival
• Results:
– No difference in healthrelated QOL
Amputation Free Survival

Adam DJ, et al. BASIL trial. Lancet 2005;366:1925–34


Drug-Eluting Technology for PAD


Paclitaxel
• Blocks proliferation of SMCs,
fibroblasts, and inflammatory cells;
blocks ECM secretion
• Very lipophilic  binds tissue at the
target site and resists wash-out
• Diffuses from endothelial surface into
medial and adventitial layers of the
arterial wall
• Deep wall tissue paclitaxel
concentration > 10x level of
endoluminal source
Paclitaxel was identified as the primary drug for DEB because of rapid uptake
and prolonged retention


Modes of Drug Delivery

Hawkins, Hennebry. Circ CV Interv 2011;4:297-302


Platforms for Drug Delivery

Hawkins, Hennebry. Circ CV Interv 2011;4:297-302

Infusion of Paclitaxel Using Irrigation Balloon
• Two cases of recurrent restenosis
– External iliac artery and SFA
• Clearway balloon used to instill paclitaxel after
PTA
• Results in a longer duration
of patency

Latif F, Hennebry TA. CCI 2008; 72:294–8


In.Pact DCB vs. PTA for FP Disease

Multicenter EU & US, randomized (2:1), single blinded
Rutherford 2-4
Tepe G, et al. London April 5, 2014


Infra-Popliteal PAD
• More often culprit for CLI
• One-year restenosis rate after PTA of long
lesions up to ~70%
• Loss of vessel patency affects the healing of
ulcers
• DES use in CLI patients is limited by:
– Complex pattern of BTK atherosclerosis
– Long, calcific stenoses/occlusions
Schmidt A, et al. CCI 2010;76:1047-1054.

Rocha-Singh KJ, et al. CCI 2007;69:910-919.
Scheinert D, et al. JACC 2012;60:2290-2295.
Rastan A, et al. JACC 2012;60:587-591.


DEBATE-BTK

Mean Lesion Length: 130mm
Liistro F et al. Circulation. 2013;128:615-621


DEB Treatment Protocol

AVOID Geographic Miss!


DEB Treatment Protocol
•
•
•
•
•

If >1 balloon used, the overlap was >5 mm
Inflation time was at least 2 min for both DEB and PTA
Coronary DES were used as a bailout
80% of the lesions were total occlusions
Subintimal recanalization was performed in one fifth

Post hoc analysis of restenosis (%) in different subgroups of the 2 study groups.

Liistro F et al. Circulation. 2013;128:615-621


DEB vs. PTA

Liistro F et al. Circulation. 2013;128:615-621


In.Pact DEEP
• Largest DEB study in BTK CLI patients
• 358 patients with Rutherford class 4 or higher at 13
European sites
• Patients randomized 2:1 to treatment with the IN.PACT
Amphirion DEB (n=239) or PTA (n=119)
• Baseline clinical, angiographic and wound characteristics
were similar across the two groups


In.Pact DEEP
DEB

PTA

P-value

Clinically-driven TLR

9.2% (18/196)

13.1% (14/107)

0.29

Late Lumen Loss

0.61±0.78

0.62±0.78

0.95

17.7% (41/232)

15.8% (18/114)

0.021 (noninferiority)
0.662 (superiority)

Primary efficacy at 12
months

Primary safety at 6months

All-cause mortality,
major amputation,
clinically-driven TLR

Medtronic voluntarily withdrew the IN.PACT Amphirion DEB from all markets in 11/2013.

Infra-genicular DES vs BMS
• Everolimus-eluting coronary DES vs. BMS for infrapopliteal PAD for CLI
• DESTINY Trial
• 140 patients at five European sites
• Primary end point: Patency at 12 months, defined as the
absence of >50% restenosis
• 74 patients treated with Xience V and 66 patients were
treated with Vision.

Bosiers M, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with
critical limb ischemia and infrapopliteal arterial occlusive Disease. J Vasc Surg 2012;55:390-9.)


Primary Patency p=0.001

Freedom from TLR p=0.001

Survival
Major amputations rare in both groups,
and no difference


What’s Missing?
Prevention of Amputation..


Preventing leg amputations in CLI with BTK DES:
PARADISE Trial

• 106 patients (118 limbs) treated with DES (nonrandomized)
• No patients excluded because of comorbidities/anatomy
• Primary end points: Major amputation and mortality
• Results:
– 3-year amputation was 6%; survival was 71%; amputation-freesurvival was 68 +/- 5%.

• Target limb revascularization in 15% of patients, and
repeat angiography in 35% of patients revealed a binary
restenosis in 12%

Feiring AJ, et al. PARADISE Trial. JACC 2010;55(15):1580-9


Feiring AJ, et al. PARADISE Trial. JACC 2010;55(15):1580-9


Observations from PARADISE Trial
3-year limb salvage/freedom from amputation: 94%
Wound healing and relief of rest pain: 93%
Trend of Improved limb salvage in Rutherford 4/5 vs. 6:
97% vs. 88%
Comparison with BASIL Study (surgery vs PTA):
– 90% of screened patients excluded (poor targets)
– Only 25% of enrolled patients had CLI


Why DEB could be better than DES?
• DEB-based drug maintains the anti-proliferative
properties
• Could be used where DES cannot be delivered

• Uptake of paclitaxel by is rapid and retained up
to 1 week
• Most appealing indication: ISR
Sustained drug release is not a requisite for the
long-lasting anti-proliferative effect of paclitaxel!

Axel DI, et al. Circulation. 1997; 96: 636–645.