The Impact of Diabetes on REvascularization

Completed

• Conditions: Diabetes Mellitus; Peripheral Arterial Disease
• Interventions: Diagnostic Test: Platelet function testing; Diagnostic Test: Vascular ultrasonography

• Registration Number: NCT03085524
• Lead Sponsor: Vanderbilt University Medical Center

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2017-03-14
• Study First Submitted QC: 2017-03-20
• Study First Posted: 2017-03-21
• Study Start: 2017-08-01
• Primary Completion: 2021-10-01
• Study Completion: 2022-10-01
• Status Verified: 2024-07
• Last Update Submitted: 2024-07-04
• Last Update Posted: 2024-07-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 215

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-

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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

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Endovascular	Vascular ultrasonography	Subjects in the BEST-CLI trial assigned to endovascular revascularization.
Surgical Bypass	Platelet function testing	Subjects in the BEST-CLI trial assigned to surgical revascularization.
Surgical Bypass	Vascular ultrasonography	Subjects in the BEST-CLI trial assigned to surgical revascularization.
Endovascular	Platelet function testing	Subjects in the BEST-CLI trial assigned to endovascular revascularization.

Primary Outcome Measures

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

Trial Locations

Locations (43)

Westchester Medical Center; 🇺🇸 Valhalla, New York, United States

Boston Medical Center; 🇺🇸 Boston, Massachusetts, United States

University of Pittsburgh Medical Center; 🇺🇸 Pittsburgh, Pennsylvania, United States

Benaroya Research Institute at Virginia Mason; 🇺🇸 Seattle, Washington, United States

San Francisco VA Medical Center; 🇺🇸 San Francisco, California, United States

Long Beach VA Medical Center; 🇺🇸 Long Beach, California, United States

University Health System: LSU Health Sciences; 🇺🇸 Shreveport, Louisiana, United States

Albany Medical Center; 🇺🇸 Albany, New York, United States

Johns Hopkins Hospital; 🇺🇸 Baltimore, Maryland, United States

Loyola University Medical Center; 🇺🇸 Chicago, Illinois, United States

University of Massachusetts Medical School; 🇺🇸 Worcester, Massachusetts, United States

New Mexico Heart Institute; 🇺🇸 Albuquerque, New Mexico, United States

The Ohio State University; 🇺🇸 Columbus, Ohio, United States

Iowa Heart Center; 🇺🇸 West Des Moines, Iowa, United States

Keck Medical Center of USC; 🇺🇸 Los Angeles, California, United States

Deborah Heart and Lung Center; 🇺🇸 Browns Mills, New Jersey, United States

Rutgers University Hospital; 🇺🇸 Newark, New Jersey, United States

University of California San Francisco Medical Center; 🇺🇸 San Francisco, California, United States

Sunnybrook Health Sciences; 🇨🇦 Toronto, Ontario, Canada

Mount Sinai Medical Center; 🇺🇸 New York, New York, United States

Decatur Memorial Hospital; 🇺🇸 Decatur, Illinois, United States

Michigan Vascular Center; 🇺🇸 Flint, Michigan, United States

Inova Heart and Vascular Institute; 🇺🇸 Falls Church, Virginia, United States

Michigan Heart - St. Joseph Mercy Health System; 🇺🇸 Ypsilanti, Michigan, United States

University of Toledo Medical Center; 🇺🇸 Toledo, Ohio, United States

Greenville Memorial Hospital; 🇺🇸 Greenville, South Carolina, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States

Dartmouth Hitchcock Medical Center; 🇺🇸 Lebanon, New Hampshire, United States

Harborview Medical Center; 🇺🇸 Seattle, Washington, United States

Chu de Quebec, St-Francois d'Assise Hospital; 🇨🇦 Québec, Quebec, Canada

The Ottawa Hospital; 🇨🇦 Ottawa, Ontario, Canada

Helsinki University Hospital; 🇫🇮 Helsinki, Finland

Gunderson Health System; 🇺🇸 La Crosse, Wisconsin, United States

St. Boniface General Hospital; 🇨🇦 Winnipeg, Manitoba, Canada

University of Colorado Hospital; 🇺🇸 Aurora, Colorado, United States

Henry Ford Hospital; 🇺🇸 Detroit, Michigan, United States

University of Nebraska Medical Center; 🇺🇸 Omaha, Nebraska, United States

Oregon Health and Science University; 🇺🇸 Portland, Oregon, United States

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of North Carolina Hospitals; 🇺🇸 Chapel Hill, North Carolina, United States

Wake Forest Baptist Health; 🇺🇸 Winston-Salem, North Carolina, United States

University of Wisconsin - Madison; 🇺🇸 Madison, Wisconsin, United States

Yale New Haven Hospital; 🇺🇸 New Haven, Connecticut, United States