The Impact of Diabetes on REvascularization (TIDE)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetes Mellitus; Peripheral Arterial Disease
• Intervention / Treatment: Diagnostic test: Platelet function testing; Diagnostic test: Vascular ultrasonography

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 Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • St. Boniface General Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4E9
      • The Ottawa Hospital
    • Toronto, Ontario, Canada, M4N 3M5
      • Sunnybrook Health Sciences
  • Quebec
    • Québec, Quebec, Canada, G1L 3P7
      • Chu de Quebec, St-Francois d'Assise Hospital
• Finland
  • Helsinki, Finland, 00029
    • Helsinki University Hospital
• United States
  • California
    • Long Beach, California, United States, 90822
      • Long Beach VA Medical Center
    • Los Angeles, California, United States, 90033
      • Keck Medical Center of USC
    • San Francisco, California, United States, 94143
      • University of California San Francisco Medical Center
    • San Francisco, California, United States, 94121
      • San Francisco VA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60153
      • Loyola University Medical Center
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
  • Iowa
    • West Des Moines, Iowa, United States, 50266
      • Iowa Heart Center
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
      • University Health System: LSU Health Sciences
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Medical School
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Flint, Michigan, United States, 48507
      • Michigan Vascular Center
    • Ypsilanti, Michigan, United States, 48197
      • Michigan Heart - St. Joseph Mercy Health System
  • Nebraska
    • Omaha, Nebraska, United States, 68106
      • University of Nebraska Medical Center
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Browns Mills, New Jersey, United States, 08015
      • Deborah Heart and Lung Center
    • Newark, New Jersey, United States, 07103
      • Rutgers University Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87102
      • New Mexico Heart Institute
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina Hospitals
    • Winston-Salem, North Carolina, United States, 28157
      • Wake Forest Baptist Health
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The Ohio State University
    • Toledo, Ohio, United States, 43604
      • University of Toledo Medical Center
  • Oregon
    • Portland, Oregon, United States, 97204
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh Medical Center
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • Greenville Memorial Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
    • Falls Church, Virginia, United States, 22042
      • Inova Heart and Vascular Institute
  • Washington
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
    • Seattle, Washington, United States, 98122
      • Benaroya Research Institute at Virginia Mason
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gunderson Health System
    • Madison, Wisconsin, United States, 53706
      • University of Wisconsin - Madison

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This ancillary study is an observational study design examining the effects of diabetes mellitus on restenosis following surgical or endovascular revascularization in CLI patients. Eligible patients will be screened according to the specified exclusion and inclusion criteria of the BEST-CLI trial.

Description

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

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Collaborators: Massachusetts General Hospital; Carelon Research

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2017
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: March 14, 2017
• First Submitted That Met QC Criteria: March 20, 2017
• First Posted (Actual): March 21, 2017

Study Record Updates

• Last Update Posted (Estimated): February 13, 2024
• Last Update Submitted That Met QC Criteria: February 10, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Endocrine System Diseases; Atherosclerosis; Diabetes Mellitus; Peripheral Arterial Disease; Peripheral Vascular Diseases
• Other Study ID Numbers: 161402

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The proposed research will include data from approximately 500 subjects enrolled in the BEST-CLI clinical trial. The final dataset will include self-reported demographic, ultrasonographic, and laboratory data from the subjects. The investigators will be collecting identifying information, but the final dataset will be stripped of identifiers prior to release for sharing. Thus, the investigators will make the data and associated documentation available to users only under a data-sharing agreement that provides for: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No