Matthew T. Menard, M.D. Stenting In-stent restenosis Brigham and - - PowerPoint PPT Presentation

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Matthew T. Menard, M.D. Brigham and Women’s Hospital

University of California San Francisco Vascular Symposium April 15, 2016

• Bittl. NEJM 1996

Stenting

In-stent restenosis

Percutaneous transluminal angioplasty (PTA) and stenting (PTAS) Barotrauma and stent placement:

• Endothelial denudation
• Subintimal hemorrhage
• Local dissection - Elastic recoil

INFLAMMATORY RESPONSE

Vascular smooth muscle cell activation Extracellular matrix formation Neointimal hyperplasia

IN-STENT RESTENOSIS

Procedure-related risk factors

Jukema et al. Nat Review 2012

Patient-specific risk factors (clinical and genetic) Lesion-specific risk factors Delivery of ionizing radiation through a directed approach

aimed at affecting local tissue.

Animal models showed that radiation inhibits the effects of

vascular smooth muscle proliferation in blood vessels undergoing angioplasty

Also thought to prevent late remodeling by inhibiting

adventitial fibrosis

Initial benefit for ISR of coronary stents was shown in several

trials (Gamma 1, Wrist, Long Wrist, Inhibit)

Further application was studied in denovo lesions in the

peripheral circulation (Vienna and Paris studies)

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Radioactive isotopes are made with neutron

bombardment of stable elements in a reactor

• r accelerator

Large unstable nucleus yearning for peace As nucleus decays emanations occur –

conservation of mass, energy

Alpha, beta, gamma, neutrinos, bosons, …

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Clinical use of radioactive sources to deliver

highly therapeutic and palliative radiation therapy to a range of targets

▪ gynecological, urological, pulmonary, head and neck, gastrointestinal, sarcoma, vascular, dermatological, endocrine disease

Photons: Extrinsic electron displaces inner shell electron Outer shell electron replaces displaced electron Energy difference between shells is ejected as chargeless

wave/particle (conservation of energy)

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γ-emitter (192Iridium)

attenuation of collagen synthesis suppression of monocyte/macrophage activity decrement or delay of smooth muscle cell proliferation Tissue growth Stent In-stent restenosis

EVBT: intraluminal delivery of radiation

approved by FDA for treatment of ISR in 2000

• 102 patients with either new or

restenotic femoropopliteal lesions.

• Randomized to angioplasty and Gamma

brachytherapy, or angioplasty alone.

• No stenting in this trial
• 6 month restenosis rate:

30% angioplasty and brachytherapy vs 57% for the angioplasty alone group.

• Brachytherapy delayed restenosis

recurrence:

17.5 months brachytherapy group vs. 7.4 months in the angioplasty alone

group

Radiology 2006 240(3) 878-844

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Distal barotrauma Proximal barotrauma

EDGE RESTENOSIS

Restenosis adjacent to the proximal and distal edges of the implanted stent (“edge effect” or “candy wrapper” phenomenon) Causes:

• 1. Radioactive dose fall-off at the stent edges
• 2. Failure of stent to treat the barotraumatized margins

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Key features:

1.

Higher radiation dose (20 gray)

2.

2 cm“safety margins” of radiation coverage proximal and distal to angioplastied/stented area

3.

Customized treatment depth: 0.5mm + radius of largest PTA balloon

Source length distal “safety margin” proximal “safety margin”

Target localization (ISR lesion, angioplasty)

Treatment type

Primary patency

Reference 6 months 1 year Repeat balloon angioplasty 27%

• Dick et al. Radiology 2008

Cutting balloon angioplasty 35%

• Dick et al. Radiology 2008

Cryoplasty 50%

• 0%

28% Karthik et al. EJVES 2007 Schmieder et al. JVS 2010 Directional atherectomy

• 54%

Zeller et al. JACC 2010 Excimer laser and stent-graft

• 48%

Laird et al. Card Cath Int 2012 PTA, laser, or excisional atherectomy 55% 47.6% Yeo et al. Card Cath Int 2011 PTA+EVBT (70%) (67%) 95.2%

• (57%)

79.8% Vienna 4 (2001) Vienna 5 (2005) Leipzig 2012

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• Retrospective, single-center review of 43 cases of EVBT for lower extremity ISR

at Brigham and Women’s Hospital between 2004-2012

• All patients were evaluated by radiation oncologist and consented for EVBT

ahead of time

• Aspirin and clopidogrel indefinitely
• Stents undergo duplex ultrasound surveillance for recurrent ISR at 1, 3, 6, 9, 12,

and 18 months and then yearly

• Primary endpoint: stent patency (primary, primary-assisted, and secondary) at 1

and 2 years

Stent patency: freedom from ≥ 50% recurrent stenosis by duplex ultrasound

Mean age (years) (± standard deviation) 67.0±11.4 Female gender, N (%) 16 (38.1%) Smoking Former Current 19 (50.0%) 6 (15.8%) Diabetes 20 (47.6%) Hypertension 36 (85.7%) Hypercholesterolemia 31 (73.8%) Chronic kidney disease (serum creatinine ≥ 2mg/dL) 7 (16.8%) End stage renal disease 2 (4.8%) Indication for original stents Claudication Critical limb ischemia 34 (81%) 8 (19%) Stent location Common iliac artery External iliac artery Superficial femoral artery Popliteal artery Combined SFA and popliteal segments 3 (7%) 6 (14%) 26 (62%) 2 (45%) 5 (12%)

SFA in-stent restenosis before PTA SFA in-stent restenosis after PTA Calibrated dummy strand for EVBT planning

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Femoropopliteal ISR lesions, N (%) 33 (76.7%)

Location of ISR: Superficial femoral artery (SFA) Popliteal artery Combined SFA and popliteal arteries

26 (60.5%) 2 (4.7%) 5 (11.9%)

Indication for EVBT: Claudication Critical stenosis on duplex Critical limb ischemia

16 (50.0%) 13 (40.6%) 3 (9.4%)

At least 1 re-intervention for ISR prior to EVBT

11 (34.4%)

Mean ABI (± SD): Pre-EVBT Post-EVBT

0.76±0.22 0.91±0.18

Additional stenting at time of EVBT

10 (31.3%)

Mean EVBT treated length, cm (± SD)

23.6±13.1

Maximum PTA balloon diameter (in mm) 4 4.5 5 6

2 (6.3%) 1 (3.1%) 17 (53.1%) 12 (37.5%)

Mean total radiation time, minutes (± SD)

16.6 ±9.8

Tibial runoff at time of EVBT (number of vessels): 1 2 3

5 (19.2%) 6 (23.1%) 15 (57.7%)

Technical success: 42/43 (97.6%) Follow-up time: 706.3±543.7 days Symptom status: Claudicants:

▪ resolved in 18/20 (85%) ▪ Improved and then recurred in 2/20

Mean ABI change: +0.14±0.23 (range -0.21-

0.84)

Recurrent ISR 50-99% stenosis after EVBT: 8/42 (19.1%)

Mean time to recurrent ISR: 505±348 days In-stent recurrence: 4/8 In-segment recurrence: 4/8

Early thrombotic occlusion: 2/42(4.7%)

Time to occlusion: 1 day, 26 days

Late thrombotic occlusion: 5/42 (11.9%)

Mean time to recurrent ISR: 708 ± 368 days

Death: 1 (possible acute coronary syndrome)

Time after EVBT 6 months (180 days) 1 year (365 days) 2 years (730 days) Primary patency 87.5% (NAR=32) 75.2% (NAR=23) 63.7% (NAR=11) Primary assisted patency 92.1% (NAR=32) 89.1% (NAR=29) 80.6% (NAR=15) Secondary patency 92.1% (NAR=33) 89.1% (NAR=29) 85.6% (NAR=16)

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Time after EVBT 6 months (180 days) 1 year (365 days) 2 years (730 days) Primary patency 86.6% (NAR=22) 78.5% (NAR=17) 66.8% (NAR=7) Primary assisted patency 89.7% (NAR=23) 85.4% (NAR=19) 76.9% (NAR=8) Secondary patency 66.8% (NAR=7) 85.4% (NAR=19) 85.4% (NAR=9) Treatment type Primary patency References 6 months 1 year 2 years Balloon angioplasty 27%

• Dick et al. Radiology 2008

Cutting balloon angioplasty 35%

• Dick et al. Radiology 2008

Cryoplasty 50%

• 0%

28%

• Karthik et al. EJVES 2007

Schmieder et al. JVS 2010 Directional atherectomy

• 54%

Zeller et al. JACC 2010 Excimer laser and stent-graft

• 48%
• Laird et al. Card Cath Int 2012

PTA, laser, or excisional atherectomy 55% 47.6% Yeo et al. Card Cath Int 2011 PTA+EVBT (70%) (67%) 95.2%

• (57%)

79.8%

• Vienna 4 (2001)

Vienna 5 (2005) Leipzig 2012

PTA+EVBT 86.6% 78.5% 66.8% Current study Retrospective review of consecutive patients who underwent

brachytherapy for angiographically proven instent restenosis, thrombosis, or occlusion

Data collected between December 2003 to February 2010 at

Brigham and Women’s Hospital cardiac catheterization laboratory.

Thirty two patients were identified including 42 lower

extremities

Performed by 3 operators Lesions included 31 SFA stents, 10 iliac stents, and 1 popliteal

stent.

Patient follow-up duration has been 5 years (and ongoing) All patients were pretreated with Aspirin 325 mg, and Plavix

load of 300-600mg pre or immediately post procedure.

Intra-arterial heparin with a goal ACT (activated clotting

time) of >250

Decisions regarding provisional brachytherapy were made

prior to cath, and were based on a combination of symptoms, ABIs, and ultrasound findings.

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Characteristic N Age (years, range) 66 (52-84) Gender (Male) 18/32(56%) CAD 24/32(75%) HTN 31/32(97%) CRI 4/32(12.5%) Smoker 26/32(81%) DM 14/32 (44%) Statin 29/32 (91%) ACEi 22/32 (69%) Index procedural Indication N Claudication 39/42 (93%) Critical limb ischemia 3/42 (7%) Index Lesion N Lesion length (mean, range) 266, 40-480 mm Chronic total occlusion 24/42 (57%) Stenosis 18/42 (43%) Index intervention N Iliac 10/42 (24%) SFA 32/42 (76%) Popliteal 1/42 (2%) Brachytherapy Indication N Claudication 40/42 (95%) Critical limb ischemia 1/42 (2.5%) Ultrasound (high grade stenosis, no symptoms) 1/42 (2.5%) Mode of index stent failure N Restenosis 31/42 (74%) Occlusion 9/42 (21%) Thrombosis 1/42 (2.5%) Unknown 1/42 (2.5%)

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Brachytherapy Details Brachytherapy dose 2000 cGy Brachytherapy radius (mean, range) 3.6mm, 3-4.5 Index Stent characteristics Index number of stents (mean, range) 2 (1-4) Index stent diameter (mean, range) 7mm (6-8) Adjunctive treatment N Angioplasty 42/42 (100%) Stenting * 10/42 Atherectomy 4/42 Laser therapy 2/42 Cutting balloon 2/42 Thrombolytics 2/42

* Stenting included strategies to prevent edge progression of lesion, exclusion of thrombus resistant to lysis, or significant lesion recoil.

Total cases 5/42 (12%) Late stent thrombosis * 2/5 Restenosis 1/5 Pseudoaneurysm ** 1/5 Total occlusion 1/5 Note: All cases presented with claudication

• *1 case due to plavix cessation, 2 years after initial stent
• ** pseudoaneurysm predated brachytherapy

Average improvement in ABIs was 0.35

(range 0.03 to 0.8) for 28 extremities with complete documentation of ABIs

Overall freedom from re-intervention by

Kaplan-Meier estimates:

100% at 1 year 97% at 2 years 74% at 5 years

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Freedom from TVR 0.25 0.50 0.75 1.00 20 40 60 Months

Kaplan Meier – Freedom from TVR after brachytherapy

Small, single-center, retrospective cohort study Treatment bias Low follow-up at later time-points Potentially non-uniform follow-up Logistic challenges to general applicability Need close collaboration between vascular surgeon

and radiation oncologist in a center with national radiation clearance

Need to reserve time and facilities in advance Staff training and availability for patient care and

transport Endovascular brachytherapy is an effective

and safe adjunctive option in patients with symptomatic lower extremity in-stent restenosis.

ISR is a pervasive challenge to the durable success of

percutaneous interventions for lower extremity chronic arterial occlusive disease

PTA and adjunctive EVBT has had limited success in the

past due to edge restenosis and late thrombotic occlusion

Updated protocol with higher radiation dose, longer

margins of radiation coverage, and customized treatment depth demonstrates potential new role of EVBT in treating lower-extremity ISR

Need a larger study with matched control cohort to

further evaluate benefit