The Impact of Diabetes on REvascularization

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.

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