Endovascular Revascularization Incorporating Infrapopliteal Coronary Drug-Eluting Stents Improves Clinical Outcomes in Patients with Critical Limb Ischemia and Tissue Loss

Journal Pre-proof Endovascular revascularization incorporating infrapopliteal coronary drug-eluting stents improves clinical outcomes in patients with critical limb ischemia and tissue loss Lauren A. Huntress, MD, Arash Fereydooni, MS, Alan Dardik, MD PhD, Naiem Nassiri, MD PII:

S0890-5096(19)30737-X

DOI:

https://doi.org/10.1016/j.avsg.2019.07.011

Reference:

AVSG 4600

To appear in:

Annals of Vascular Surgery

Received Date: 2 June 2019 Revised Date:

11 July 2019

Accepted Date: 12 July 2019

Please cite this article as: Huntress LA, Fereydooni A, Dardik A, Nassiri N, Endovascular revascularization incorporating infrapopliteal coronary drug-eluting stents improves clinical outcomes in patients with critical limb ischemia and tissue loss, Annals of Vascular Surgery (2019), doi: https:// doi.org/10.1016/j.avsg.2019.07.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc.

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Endovascular revascularization incorporating infrapopliteal coronary drug-eluting stents improves clinical outcomes in patients with critical limb ischemia and tissue loss Lauren A. Huntress MD1, Arash Fereydooni MS2, Alan Dardik MD PhD2,3, Naiem Nassiri MD2,3 1. Department of Surgery, Division of Vascular Surgery, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ 2. Department of Surgery, Division of Vascular & Endovascular Surgery, Yale University School of Medicine, New Haven, CT 3. VA Connecticut Healthcare System, West Haven, CT This manuscript was previously presented at AVAS meeting in Miami, Florida, May 2018. Corresponding Author: Naiem Nassiri, MD, RPVI Associate Professor of Surgery (Vascular) Division of Vascular Surgery, Department of Surgery, Yale University School of Medicine Chief, Vascular & Endovascular Surgery, VA Connecticut Healthcare Systems [email protected] Word Count: 1,930 Keywords: drug-eluting stents, WIfI Score, critical limb ischemia, tibial, infrapopliteal Financial disclosure: The authors have no disclosures to report.

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Abstract 1

Purpose: Critical limb ischemia (CLI) involving infrapopliteal arterial atherosclerosis and tissue

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loss remains a formidable clinical scenario with significant morbidity and mortality. Despite

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level IA evidence, tibial revascularization with coronary drug-eluting stents (DES) remains a

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seldom-used technique in the United States due, in part, to lack of a Food and Drug

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Administration (FDA)-approved indication and dedicated stent technology for infrapopliteal

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application. Furthermore, follow-up data beyond 1 year remain scarce and further evidence for

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improvement in clinical outcomes using this technique is needed. Herein, we present our multi-

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institutional experience with endovascular revascularization of patients with CLI and tissue loss

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using coronary DES for infrapopliteal lesions of appropriate dimensions; and the Wound,

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Ischemia, foot Infection (WIfI) score as supportive evidence for improvement in clinical

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outcomes.

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Methods: In this retrospective study, 40 sequential tibial revascularization procedures performed

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in 32 patients with CLI were reviewed. Outcomes including changes in WIfI scores, patency

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rates, freedom from major amputation, target lesion recurrence, and all-cause mortality were

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analyzed. Average follow-up was 19.3 months (interquartile range 7-27.1 months).

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Results: Freedom from major amputation was 88.6%. One-year primary patency was 90.3%.

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Mean ABIs increased after revascularization (0.57 ± 0.26 to 0.97 ± 0.26; p=0.03). All

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components of the WIfI score significantly improved after revascularization (W:1.9 to 1.1,

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p=0.03; I:2.0 to 0.6, p=0.001 and fI:1.5 to 0.8, p=0.01). WIfI risk of major amputation score

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before revascularization was 3.58 ± 0.75 (high-risk) which was reduced to 2.04 ± 1.31 (low-risk;

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p < 0.001). One-year survival rate was 90.6%.

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Conclusions: Coronary DES continue to demonstrate promising primary patency and limb

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salvage rates in appropriately selected patients undergoing multi-level endovascular

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revascularization for CLI and tissue loss. In addition to its value as a predictor for major

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amputation and revascularization benefit, the WIfI score can also serve as a multi-component

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tool for objective assessment of outcomes following revascularization.

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Introduction Critical limb ischemia (CLI) involving infrapopliteal pathology remains a formidable

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clinical scenario with significant patient morbidity and mortality.1 While autogenous bypass is

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heralded as the gold standard for infrapopliteal revascularization, advances in endovascular and

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drug-eluting technology have been promising. Several meta-analyses and multicenter

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randomized controlled trials have shown superior results for the use of coronary drug-eluting

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stents (DES) with regards to primary patency and limb salvage rates when compared to other

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endovascular modalities.2-9 Despite these promising results, infrapopliteal coronary DES remain

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seldom used in the endovascular revascularization of patients with CLI. This is due, in part, to

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lack of a Food and Drug Administration (FDA) approval and dedicated stent design for

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infrapopliteal application. Furthermore, follow-up data beyond 12 months remain scarce and

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improvements in clinical outcomes need further verification.

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The growing utility of this promising technology can serve as a learning platform for

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upcoming safety and feasibility trials for dedicated infrapopliteal drug-eluting stent design and

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provide a growingly more viable, less invasive alternative and adjunct to distal bypass surgery.

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Herein, therefore, we share our multi-institutional experience with the endovascular

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revascularization of patients with CLI and tissue loss incorporating coronary DES for

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infrapopliteal revascularization; and the Wound, Ischemia, and foot Infection (WIfI) score as a

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multi-component tool for objective assessment and of clinical outcomes.

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Methods

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Study Design

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Medical records of 32 patients who underwent 40 tibial revascularization procedures for

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peripheral arterial disease over a 4-year period were retrospectively reviewed. All stenting

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procedures in this study were performed as the primary treatment of tibial vessels and no prior

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tibial interventions were performed in this cohort. Informed consent was obtained from all

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patients as per institutional review board protocol. The Society for Vascular Surgery WIfI

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system10 was utilized to objectively evaluate the limb prior to intervention. Wound

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characteristics, degree of ischemia, and presence of local and/or systemic infection were scored

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on a scale of 0-3. The risk of 1-year amputation and benefit of revascularization were derived

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using the WIfI score combinations, as published by Mills et al,10 which include “very low risk,”

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“low risk,” “moderate risk,” and “high risk.” The risk category determines the clinical disease

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stage. Patients in the “very low risk category” would be deemed a clinical stage 1 for risk of

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major amputation at one year.

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All concomitant aortoiliac or femoropopliteal lesions were addressed before or at the time

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of infrapopliteal intervention. Angiography determined anatomical suitability for coronary DES

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deployment with the goal of achieving unimpeded, in-line flow to the foot via at least one run-off

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vessel. Long segment occlusions beyond 15 cm and contiguous, multilevel occlusive lesions

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involving the femoropopliteal level were excluded and underwent alternative modes of

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revascularization. In patients with occluded stents, no reintervention was performed. If the

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wounds had healed, stent salvage was deemed unnecessary; if patients had worsening critical

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limb ischemia, surgical bypass was considered. Outcomes including changes in WIfI scores,

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patency rates, freedom from major amputation, target lesion recurrence, and all-cause mortality

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were analyzed.

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Following intervention, all patients were discharged on dual antiplatelet therapy

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consisting of aspirin (81 mg daily) indefinitely and clopidogrel (75 mg daily) for a minimum of

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12 months.11 Duplex ultrasound surveillance at one, three, and six months, and annually

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thereafter, were performed to determine stent patency.

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Statistical analysis Discrete and categorical variables were presented as numbers (percentages), while

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continuous variables were presented as mean ± standard deviation. The χ 2 or Fisher exact, and

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Student t test were used to establish statistical significance. Primary patency, amputation-free

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survival and overall survival rates were estimated with Kaplan-Meier survival analysis. Stepwise

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regression analysis with the Cox proportional hazards model was employed for the identification

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of any independent risk factors influencing primary patency, freedom from major amputation

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and amputation-free survival. A P value < .05 was considered statistically significant. All

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statistical analyses were performed using Prism 8 software (GraphPad Software, Inc., La Jolla,

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CA).

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Results Seventy-eight coronary DES were deployed in 32 patients with CLI and tissue loss over a

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4-year time period (Figures 1 and 2). Patient demographics are defined in Table 1. Average

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lesion length was 34.0± 21.0 mm and, given the limited stent lengths available, an average of

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2.1± 1.0 stents was deployed per patient. The distribution of treated lesion locations is

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delineated in Table 2.

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Mean follow-up length was 19.3 months (interquartile range 7-27.1 months).When

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compressible and calculable, average preoperative ankle brachial indices (ABI) were 0.57 ± 0.26

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and postoperative ABIs were 0.97 ± 0.26 (p=0.03). When ABIs were unobtainable, toe pressures

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and/or transcutaneous oximetry were utilized to derive the ischemia component of the WIfI

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score. Average preoperative WIfI scores (Table 3) were W:1.9, I:2.0, fI:1.5. When determining

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pre-intervention one-year risk of major amputation, the average clinical stage was 3.6 ± 0.75,

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translating to “high-risk” of major amputation at one year. WIfI score clinical score

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subcategories are also delineated in Table 1. Regarding potential benefit to revascularization,

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the average clinical stage was 3.5 ± 0.94, translating to “high benefit.” Average postoperative

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WIfI scores were W:1.1, I:0.6, fI:0.8 (p= 0.03, p=0.001, p=0.01, respectively). In patients

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suffering from ulcers at baseline, wound healing was observed in 27 (84.4%) patients at 1-year

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follow-up.

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A total of 12 stents occluded in 5 patients, yielding an overall 15.4% failure rate at the

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time of last follow-up. Kaplan-Meier estimates for primary patency were 90.3% at one year,

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80.3% at two years, 74.4% at three years and four years (Figure 3A). Freedom from major

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amputation was 88.6% with two patients requiring below-knee-amputation and two patients

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requiring above-knee amputation. Kaplan-Meier estimate for amputation-free survival was 81%

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at one year. No patients required an open bypass in the follow-up period. Four patients died

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secondary to myocardial infarction and one secondary to hypoxic respiratory failure. The

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survival rates were 90.6% at one year, 80.1% at two years, 74.4% at three years (Figure 3C).

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No significant interaction was observed between baseline patient characteristics and primary patency and major amputation rate in the Cox regression model. The regression

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modeling, however, identified age (p=0.031) and chronic kidney disease (p=0.011) as

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independent predictors of survival.

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Discussion

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In this series of patients with CLI and tissue loss undergoing endovascular

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revascularization incorporating infrapopliteal coronary DES, we present a freedom from major

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amputation rate of 88.6%, 1-year primary patency rate of 90.3%, and 1-year amputation-free

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survival of 81%. Furthermore, each individual component of the WIfI score significantly

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improved along with significant reductions in major amputation scores. This provides further

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evidence in support of the revascularization benefit and limb salvage potential of an

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endovascular approach that incorporates coronary DES below the knee in CLI patients with short

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(<150 mm) infrapopliteal atherosclerotic lesions and tissue loss.

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To date, no direct comparison of endovascular revascularization incorporating

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infrapopliteal coronary DES to autogenous distal bypass has been performed. Through a number

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of multicenter randomized controlled trials, however, infrapopliteal coronary DES have proven

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superior to other endovascular revascularization techniques such as bare-metal stenting (BMS),

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plain balloon angioplasty (PBA), PBA + BMS, and drug-coated balloon angioplasty in patients

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with short (<150 mm) infrapopliteal atherosclerotic lesions.3, 5, 7 In the ACHILLES trial,

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coronary DES demonstrated higher device success rates (95.5% vs 58.2%, P = 0.001), lower 12-

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month restenosis rates (22.4% vs 41.9%, P = 0.019), superior patency (75.0% vs 57.1%, P

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=0.025), and improved Rutherford class in comparison to PBA of infrapopliteal arteries.

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However, revascularization and amputation rates were similar between the two arms. The

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YUKON BTK2 and DESTINY3 trials demonstrated that coronary DES had improved primary

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patency, reduced target lesion recurrence, and had lower rates of major amputation when

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compared to BMS. The IDEAS trial showed that paclitaxel-coated balloon PTA had

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significantly increased rates of target lesion re-stenosis (58%) when compared to coronary DES

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(28%).7 The PADI trial demonstrated superior 6-month patency and reduced risk of major

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amputation with coronary DES vs. PTA + BMS in patients with CLI.5 Long-term follow-up was

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consistent with short-term findings, with improved amputation- and event-free survival in the

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coronary DES arm (31.8% vs 20.4%; P=0.043, and 26.2% vs 15.3%; P=0.041, respectively).

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While limited by its retrospective nature and relatively small sample size, our current series

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verifies the high primary patency and freedom from major amputation rates of infrapopliteal

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coronary DES at a mean follow-up of 19.3 months while maintaining low rates of target lesion

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restenosis in anatomically suitable patients. Furthermore, we have used the WIfI score as a

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multi-component objective tool for on-going assessment of clinical outcomes following

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revascularization. Each individual component of the WIfI score remained significantly improved

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at the time of last follow-up along with maintained reduction in predicted risk for major

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amputation. This expands the utility of the WIfI score beyond merely a prognostic tool. The

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WIfI score, therefore, may serve as an additional endpoint for comparison between various

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revascularization modalities for future prospective randomized trials.

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All stents used in the series were polymer-containing, balloon-expandable coronary stents

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eluting mTOR pathway inhibitors (everolimus or zotarolimus). It is important to distinguish

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between drug-eluting and drug-coated stent technology. The former contains a polymer matrix

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(comprised of silicone, cellulose ester, etc.) saturated with an immunosuppressant drug and

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allows targeted drug delivery for prolonged periods of time. Without this matrix, the stent is

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merely drug-coated with limited duration of local drug delivery. This may be, in part,

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responsible for the persistently high primary patency rates observed across various trials utilizing

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drug-eluting technology via polymer matrices. Although the cost per unit of coronary DES is higher

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in comparison with other alternative treatment options, the overall healthcare cost may be lower by

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enhancing primary patency and limb salvage rates. Coronary DES is not available in surgical

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operating rooms and pre-procedural coordination with the interventional cardiology inventory is

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necessary. It is important to note that the currently approved local drug delivering stents for

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femoropopliteal deployment lack polymer matrices and are, therefore, more appropriately

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labeled as drug-coated rather than drug-eluting stents. Furthermore, recent meta-analyses on

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paclitaxel-coated balloons and stents have raised concerns regarding all-cause mortality with this

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antimitotic medication and the FDA has issued a statement advising limited use.12, 13 Until

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further investigation, these limitations on paclitaxel-mediated drug-coated technology may

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provide an opportunity for expanded utility of non-paclitaxel mediated, polymer-containing

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drug-eluting stents for infrapopliteal revascularization despite lack of formal FDA approval and

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dedicated peripheral stent design. Furthermore, the robust existing clinical evidence supporting

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infrapopliteal coronary DES use warrants prospective randomized comparison with autogenous

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distal surgical bypass. Subgroup analyses of the Best Endovascular Versus Best Surgical

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Therapy for Patients with Critical Limb Ischemia (BEST-CLI) Trial may provide further

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insight.14

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We encourage the continued use of the WIfI Score as an objective assessment of clinical

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outcomes when evaluating new endovascular technologies in patients with CLI.10, 15, 16

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Successful wound healing, which is the indication for many infrapopliteal revascularization

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procedures, is infrequently studied as a clinical outcome, and concomitant use of the WIfI score

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could provide a more comprehensive pre- and post-intervention wound assessment for future

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studies.

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There are several limitations to this study. This is a non-randomized, retrospective study,

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and a relatively small number of patients were investigated. The regression model did not

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identify more predictors of primary patency and amputation free survival, likely due to the small

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number of patients. The majority of the patients were male (80%) and clinical outcomes results

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may not be generalizable to a population with higher female representation.

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Conclusions In appropriately selected patients with CLI and tissue loss, endovascular

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revascularization with incorporation of infrapopliteal coronary DES significantly improves all

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elements of the WIfI score including the overall predicted risk of major amputation. Primary

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patency and freedom from major amputation rates for endovascular revascularization using

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infrapopliteal coronary DES at a mean follow-up of 19.3 months remain high. Dedicated

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infrapopliteal stent design and configuration may further enhance outcomes and be applied to a

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larger subset of patients. Utilization of WIfI score is indicated for future studies assessing wound

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prognosis.

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Acknowledgments/funding: None

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References

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1. Jaff MR, White CJ, Hiatt WR, et al. An Update on Methods for Revascularization and Expansion of the TASC Lesion Classification to Include Below-the-Knee Arteries: A Supplement to the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II): The TASC Steering Comittee(.). Annals of vascular diseases. 2015; 8: 343-57. 2. Rastan A, Brechtel K, Krankenberg H, et al. Sirolimus-eluting stents for treatment of infrapopliteal arteries reduce clinical event rate compared to bare-metal stents: long-term results from a randomized trial. Journal of the American College of Cardiology. 2012; 60: 587-91. 3. Bosiers M, Scheinert D, Peeters P, et al. Randomized comparison of everolimus-eluting versus bare-metal stents in patients with critical limb ischemia and infrapopliteal arterial occlusive disease. Journal of vascular surgery. 2012; 55: 390-8. 4. Scheinert D, Katsanos K, Zeller T, et al. A prospective randomized multicenter comparison of balloon angioplasty and infrapopliteal stenting with the sirolimus-eluting stent in patients with ischemic peripheral arterial disease: 1-year results from the ACHILLES trial. Journal of the American College of Cardiology. 2012; 60: 2290-5. 5. Spreen MI, Martens JM, Hansen BE, et al. Percutaneous Transluminal Angioplasty and DrugEluting Stents for Infrapopliteal Lesions in Critical Limb Ischemia (PADI) Trial. Circulation Cardiovascular interventions. 2016; 9: e002376. 6. Spiliopoulos S, Fragkos G, Katsanos K, Diamantopoulos A, Karnabatidis D and Siablis D. Longterm Outcomes Following Primary Drug-Eluting Stenting of Infrapopliteal Bifurcations. Journal of Endovascular Therapy. 2012; 19: 788-96. 7. Siablis D, Kitrou PM, Spiliopoulos S, Katsanos K and Karnabatidis D. Paclitaxel-coated balloon angioplasty versus drug-eluting stenting for the treatment of infrapopliteal long-segment arterial occlusive disease: the IDEAS randomized controlled trial. JACC Cardiovascular interventions. 2014; 7: 1048-56. 8. Spiliopoulos S, Vasiniotis Kamarinos N and Brountzos E. Current evidence of drug-elution therapy for infrapopliteal arterial disease. World journal of cardiology. 2019; 11: 13-23. 9. Katsanos K, Spiliopoulos S, Diamantopoulos A, Karnabatidis D, Sabharwal T and Siablis D. Systematic review of infrapopliteal drug-eluting stents: a meta-analysis of randomized controlled trials. Cardiovascular and interventional radiology. 2013; 36: 645-58. 10. Mills JL, Sr., Conte MS, Armstrong DG, et al. The Society for Vascular Surgery Lower Extremity Threatened Limb Classification System: risk stratification based on wound, ischemia, and foot infection (WIfI). Journal of vascular surgery. 2014; 59: 220-34.e1-2. 11. Steinhubl SR, Berger PB, Mann JT, 3rd, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. Jama. 2002; 288: 2411-20. 12. Katsanos K, Spiliopoulos S, Kitrou P, Krokidis M and Karnabatidis D. Risk of Death Following Application of Paclitaxel-Coated Balloons and Stents in the Femoropopliteal Artery of the Leg: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Journal of the American Heart Association. 2018; 7: e011245. 13. UPDATE: Treatment of Peripheral Arterial Disease with Paclitaxel-Coated Balloons and Paclitaxel-Eluting Stents Potentially Associated with Increased Mortality - Letter to Health Care Providers. In: Administration USFaD, (ed.). Letter to Health Care Providers ed. 2019. 14. Menard MT, Farber A, Assmann SF, et al. Design and Rationale of the Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial. Journal of the American Heart Association. 2016; 5.

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15. Zhan LX, Branco BC, Armstrong DG and Mills JL, Sr. The Society for Vascular Surgery lower extremity threatened limb classification system based on Wound, Ischemia, and foot Infection (WIfI) correlates with risk of major amputation and time to wound healing. Journal of vascular surgery. 2015; 61: 939-44. 16. Mayor J, Chung J, Zhang Q, et al. Using the Society for Vascular Surgery Wound, Ischemia, and foot Infection classification to identify patients most likely to benefit from revascularization. Journal of vascular surgery. 2019.

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Figure Legends

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Figure 1. A, B) High-grade stenosis of single vessel peroneal runoff extending into the distal anastomosis

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of the distal aspect of femoro-peroneal bypass graft in a patient with ongoing CLI and tissue loss.

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Revascularization with three CDES and restoration of inline flow was achieved. C, D) Extensive

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contiguous high grade stenoses of the peroneal artery in a patient with single vessel run-off.

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Revascularization with four CDES with minimal overlap was achieved. E, F) Occlusion of the distal PT

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artery in a patient with CLI and tissue loss and absent inline flow to the plantar arch. Restoration of inline

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flow is achieved with two CDES extending from the distal PT into the proximal plantar arteries. Pedal

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arch revascularization and augmentation of flow is noted.

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Figure 2. A) Extensive pedal tissue loss and chronic osteomyelitis in a patient with multi-level disease.

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B) Inline flow revascularization including CDE tibial revascularization led to significantly improved

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pedal perfusion with subsequent granulation tissue formation and resolution of chronic osteomyelitis. C)

269

Satisfactory limb salvage was achieved.

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Figure 3. Kaplan-Meier curves show (A) primary patency rate of CDES used in tibial revascularization,

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(B) amputation fee survival and (C) overall survival in patients undergoing tibial revascularization with

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CDES.

Table 1. Baseline characteristics of patients Patient Data Stratified by WIfI Score Clinical Stage WIfI Score Clinical Stage Very Low Moderate Low Risk (2) Risk (3) Risk (1) 0 (0%) 5 (16%) 4 (12%) No. of patients -68.6 ± 66.8 ± Age, mean (SD), years 15.3 12.3 Sex Male 0 (0%) 2 (40%) 4 (100%) Female 0 (0%) 3 (60%) 0 (0%) Comorbidities Type II Diabetes 0 (0%) 2 (40%) 4 (100%) Hypertension 0 (0%) 3 (60%) 4 (100%) Chronic kidney disease 0 (0%) 1 (20%) 2 (50%) Dyslipidemia 0 (0%) 5 (100%) 4 (100%) Coronary Artery Disease 0 (0%) 4 (80%) 4 (100%) Prior CABG/PCI 0 (0%) 1(20%) 1 (25%) Hemodialysis 0 (0%) 0 (0%) 0 (0%) 0 (0%) 5 (100%) 4 (100%) Tobacco Use Presenting Symptoms Ulceration 0 (0%) 5 (100%) 4 (100%) Gangrene 0 (0%) 1 (20% 3 (75%)

High Risk Total (4) 23 (72%) 68.1 ± 10.0

32 67.2 ± 10.7

19 (86%) 3 (14%)

32 (80%) 32 (20%)

23 (100%) 19 (86%) 12 (52%) 23 (100%) 15 (68%) 4 (18%) 2 (9%) 16 (72%)

27 (84%) 26 (84%) 15 (48%) 31 (100%) 22 (71%) 6/22 (27%) 32 (6%) 32 (74%)

23 (100%) 32(100%) 11 (35%) 15 (48%)

Table 2. Characteristics of devices sued and treated lesions Stent Design and Lesion Characteristics Number (%) Stent design XIENCE Alpine (everolimus-eluting) 6/78 (8%) SYNERGY™ (everolimus-eluting) 9/78 (12%) PROMUS® (everolimus-eluting) 63/78 (81%) Resolute Onyx™ (zotarolimus-eluting) 1/78 (1%) Lesion Distribution Tibioperoneal trunk 18/55 (33%) Peroneal artery 11/55 (20%) Anterior tibial artery 14/55 (25%) Posterior tibial artery 8/55 (15%) Autogenous bypass graft 3/55 (5%) Plantar artery 1/55 (2%) 34.0, (21.1) Lesion length, mean (SD), mm 2.1, (1.0) No. stents per patient, mean (SD), mm

Table 3. Pre- and Post-Operative Wound Severity Scores Pre- and post- operative WIfI scores Pre-Operative Post-Operative WIfI Score Wound 1.90 ± 0.84 1.16 ±1.08 Ischemia 2.02 ± 0.98 0.62 ± 1.13 Foot Infection 1.45 ± 0.87 0.81 ± 1.14 0.59 ± 0.23 0.96 ± 0.22 Ankle Brachial Index 2.04 ± 1.31 WIfI Score Risk of Major Amputation 3.58 ± 0.75 (High) (Low) (Clinical Stage) 3.45 ± 0.94 0.92 ± 1.6 WIfI Score Benefit to (High) (Low) Revascularization (Clinical Stage)

P Value 0.03 0.001 0.01 0.001 0.0001 0.0001