The Impact of Diabetes on REvascularization

Study Overview
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Brief Summary
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The presence of foot symptoms at rest or tissue necrosis in patients with peripheral artery disease is a medical urgency and represents a state of critical limb ischemia (CLI) where the risk of amputation, in the absence of revascularization, is high. No trial conducted to date in peripheral revascularization has determined the effect of diabetes on mechanism of revascularization failure. Therefore, this trial represents a unique opportunity to investigate the mechanisms by which diabetes affects surgical and endovascular revascularization procedures with the long-term goal of improving outcomes in CLI.

Detailed Description
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Peripheral artery disease is a condition defined by marked accumulation of atherosclerotic plaque below the distal aorta that reduces lower limb arterial perfusion. Blood flow reductions may be inadequate for exercising limbs and cause ischemic muscle pain, called intermitted claudication, or, in severe cases, the reduction may be inadequate for basal metabolism and cause pain at rest, ulceration, or gangrene. The presence of symptoms at rest or tissue necrosis is a medical urgency and represents a state of critical limb ischemia (CLI) where the risk of amputation, in the absence of revascularization, is high. The ageing of the population and the increasing prevalence of diabetes mellitus ensures this population will continue to grow in the foreseeable future. The impact of diabetes, however, is not limited to PAD incidence. Diabetic patients represent a particularly vulnerable subset of PAD patients and have a four-fold risk of CLI compared to non-diabetic patients. Indeed, in previous studies of CLI, more than half of patients have diabetes. As a result, the combination of diabetes and PAD accounts for more than half of non-traumatic amputations in the United States. Diabetic patients often present with foot ulcerations as their first manifestation of PAD and have challenging anatomy for revascularization. Failed vascular reconstructions, both endovascular or surgical, often result in additional tissue loss and transtibial amputations. Despite these challenges, the mechanisms of restenosis and the impact of diabetes have not been well explored for both types of revascularization in patients with CLI. The BEST-CLI trial is a multi-center, randomized, comparative effectiveness trial comparing open surgical bypass therapy to endovascular therapy in CLI patients with a composite clinical endpoint denoted as Major Adverse Limb Event free survival (MALE-free survival). However, the BEST-CLI trial does not study the mechanisms by which revascularization may fail. This proposal will extend the novel clinical work of the BEST-CLI trial by studying the mechanisms of bypass vein graft and stent failure. The investigators will adjudicate the mode of revascularization (vein graft or stent) in a central core laboratory, measure systemic markers of diabetic dysmetabolism including inflammation, insulin resistance, adverse adipokine expression, poor nutrition, and renal dysfunction, and begin to study the association of these factors with graft failure. Indeed, no trial conducted to date in either coronary or peripheral revascularization has determined the mechanism of revascularization failure, the impact of diabetes, nor the relationship between conduit patency and clinical outcomes. Therefore, this trial represents a unique opportunity to investigate the mechanisms by which diabetes affects surgical and endovascular revascularization procedures.

Official Title
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The Impact of Diabetes on REvascularization

Conditions
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Peripheral Arterial Disease, Diabetes Mellitus

Intervention / Treatment
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* Diagnostic Test: Platelet function testing
* Diagnostic Test: Vascular ultrasonography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 35 years or older Atherosclerotic, infrainguinal PAD CLI, defined as arterial insufficiency with gangrene, non-healing ischemic ulcer, or rest pain, consistent with Rutherford classes 4-6 Candidate for either open or endovascular infrainguinal revascularization as judged by the treating investigators Adequate inflow into the index femoral artery Adequate popliteal, tibial, or pedal revascularization target Willing to comply with protocol, attend follow-up appointments, complete all study assessments, and provide informed consent Endovascular revascularization with a stent Surgical revascularization with a vein graft- Exclusion Criteria: Femoropopliteal disease pattern consistent with TASC IIA Complete occlusion of the iliac artery Aortoiliac occlusive disease or severe common femoral artery disease Presence of a femoral, popliteal or tibial aneurysm of the index limb Life expectancy less than 2 years Deemed excessive risk for surgical bypass A vascular disease prognosis that includes an anticipated above ankle amputation on index limb within 4 weeks of index procedure Renal dysfunction defined as MDRD eGFR ≤ 30ml/min/173 m2 at the time of screening Currently on dialysis or history of a renal transplant A documented hypercoagulable state Nonatherosclerotic occlusive disease Any prior infrainguinal revascularization Current immuno-suppressive medication, chemotherapy or radiation therapy Absolute contraindication to iodinated contrast

Ages Eligible for Study
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Minimum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Surgical Bypass<br>Subjects in the BEST-CLI trial assigned to surgical revascularization. | Diagnostic Test: Platelet function testing<br>* The investigators will test platelet reactivity at the beginning and midpoint of the first year after revascularization<br>Diagnostic Test: Vascular ultrasonography<br>* The investigators will test bypass graft and stent patency at 30 days, 6 months, and 1 year.<br>|
| Endovascular<br>Subjects in the BEST-CLI trial assigned to endovascular revascularization. | Diagnostic Test: Platelet function testing<br>* The investigators will test platelet reactivity at the beginning and midpoint of the first year after revascularization<br>Diagnostic Test: Vascular ultrasonography<br>* The investigators will test bypass graft and stent patency at 30 days, 6 months, and 1 year.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Adverse Limb Event - free survival | The combination of amputation, surgical revascularization, thrombectomy, thrombosis, interposition graft, or death | 1 year | 
| Restenosis | Greater than 50% stenosis as determined by peak systolic velocity ratio of >2.4 | 1 year |