Matthew T. Menard, M.D. Brigham and Women s Hospital

Transkript

1 Matthew T. Menard, M.D. Brigham and Women s Hospital University of California San Francisco Vascular Symposium April 15, 2016 Stenting In-stent restenosis Bittl. EJM 1996 Percutaneous transluminal angioplasty (PTA) and stenting (PTAS) Barotrauma and stent placement: - Endothelial denudation - Subintimal hemorrhage - Local dissection - Elastic recoil IFLAMMATORY RESPOSE Vascular smooth muscle cell activation eointimal hyperplasia Extracellular matrix formation I-STET RESTEOSIS Procedure-related risk factors Patient-specific risk factors (clinical and genetic) Lesion-specific risk factors Jukema et al. at Review 2012 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) 1

2 Radioactive isotopes are made with neutron bombardment of stable elements in a reactor or accelerator Large unstable nucleus yearning for peace As nucleus decays emanations occur conservation of mass, energy Alpha, beta, gamma, neutrinos, bosons, 6 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) 7 EVBT: intraluminal delivery of radiation Stent In-stent restenosis Tissue growth γ-emitter ( 192 Iridium) attenuation of collagen synthesis suppression of monocyte/macrophage activity decrement or delay of smooth muscle cell proliferation approved by FDA for treatment of ISR in patients with either new or restenotic femoropopliteal lesions. Randomized to angioplasty and Gamma brachytherapy, or angioplasty alone. o 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 (3)

3 EDGE RESTEOSIS 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 Distal barotrauma Proximal barotrauma 11 Key features: distal safety margin Source length Target localization (ISR lesion, angioplasty) 1. Higher radiation dose (20 gray) proximal safety margin 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 Treatment type Primary 6 months 1 year Reference 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 PTA, laser, or excisional atherectomy PTA+EVBT 48% Laird et al. Card Cath Int % 47.6% Yeo et al. Card Cath Int 2011 (70%) (67%) 95.2% (57%) 79.8% Vienna 4 (2001) Vienna 5 (2005) Leipzig

4 Retrospective, single-center review of 43 cases of EVBT for lower extremity ISR at Brigham and Women s Hospital between 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 (primary, primary-assisted, and secondary) at 1 and 2 years Stent : freedom from 50% recurrent stenosis by duplex ultrasound Mean age (years) (± standard deviation) 67.0±11.4 Female gender, (%) 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 Stent location Common iliac artery External iliac artery Superficial femoral artery Popliteal artery Combined SFA and popliteal segments 34 (81%) 8 (19%) 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 4

5 Femoropopliteal ISR lesions, (%) 33 (76.7%) Location of ISR: Superficial femoral artery (SFA) Popliteal artery Combined SFA and popliteal arteries Indication for EVBT: Claudication Critical stenosis on duplex Critical limb ischemia 26 (60.5%) 2 (4.7%) 5 (11.9%) 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± ±0.18 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) (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): (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 ) 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 Primary Primary assisted Secondary 6 months (180 days) 87.5% (AR=32) 92.1% (AR=32) 92.1% (AR=33) 1 year (365 days) 75.2% (AR=23) 89.1% (AR=29) 89.1% (AR=29) 2 years (730 days) 63.7% (AR=11) 80.6% (AR=15) 85.6% (AR=16) 5

6 Time after EVBT Primary Primary assisted Secondary 6 months (180 days) 86.6% (AR=22) 89.7% (AR=23) 66.8% (AR=7) 1 year (365 days) 78.5% (AR=17) 85.4% (AR=19) 85.4% (AR=19) 2 years (730 days) 66.8% (AR=7) 76.9% (AR=8) 85.4% (AR=9) Treatment type Primary 6 months 1 year 2 years References Balloon angioplasty 27% Dick et al. Radiology 2008 Cutting balloon angioplasty Cryoplasty 35% Dick et al. Radiology % 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 PTA, laser, or excisional atherectomy 48% Laird et al. Card Cath Int % 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 mg 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. 6

7 Characteristic Age (years, range) 66 (52-84) Gender (Male) 18/32(56%) CAD 24/32(75%) HT 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 Claudication 39/42 (93%) Critical limb ischemia 3/42 (7%) Index intervention Iliac 10/42 (24%) SFA 32/42 (76%) Popliteal 1/42 (2%) Index Lesion Lesion length (mean, range) 266, mm Chronic total occlusion 24/42 (57%) Stenosis 18/42 (43%) Brachytherapy Indication Claudication 40/42 (95%) Critical limb ischemia 1/42 (2.5%) Ultrasound (high grade stenosis, no symptoms) Mode of index stent failure 1/42 (2.5%) Restenosis 31/42 (74%) Occlusion 9/42 (21%) Thrombosis 1/42 (2.5%) Unknown 1/42 (2.5%) 7

8 Index Stent characteristics Adjunctive treatment Index number of stents (mean, range) 2 (1-4) Index stent diameter (mean, range) 7mm (6-8) Angioplasty 42/42 (100%) Stenting * 10/42 Atherectomy 4/42 Brachytherapy Details Brachytherapy dose 2000 cgy Laser therapy 2/42 Cutting balloon 2/42 Thrombolytics 2/42 Brachytherapy radius (mean, range) 3.6mm, * 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 *1 case due to plavix cessation, 2 years after initial stent ** pseudoaneurysm predated brachytherapy ote: All cases presented with claudication 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 8

9 Kaplan Meier Freedom from TVR after brachytherapy Freedom from TVR Months 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 eed close collaboration between vascular surgeon and radiation oncologist in a center with national radiation clearance eed 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 eed a larger study with matched control cohort to further evaluate benefit 9