Clinical Implications of Peripheral Plaque Morphology

Peripheral Artery Disease involves a buildup of fatty deposits (plaque) within blood vessels that can restrict blood flow. Patients who have PAD and claudication (pain in legs during exercise due to poor blood circulation) may be eligible for this clinical trial. Three primary hypotheses will be tested in this study: (1) IVUS (Intravascular Ultrasound)combined with advanced digital image and signal processing provides a sensitive method to determine plaque geometry and composition in the human peripheral artery wall; (2) IVUS can discern specific arterial wall morphology, providing data that can be used to identify plaques that predispose the patient to late complications; and (3) IVUS-derived plaque structure can be used to predict responders and non-responders to pharmacologic therapy and percutaneous endovascular interventions. These hypotheses will be tested as follows: (1) custom engineered IVUS analysis software will be used to describe the geometry, composition, and spatial component relationships of the vessel, (2) the morphology of lower extremity arterial plaque, as determined by IVUS, will be correlated with baseline clinical characteristics of subjects, and (3) the effects on plaque morphology after long term treatment with antihyperlipidemics will be determined.

Study Overview

• Status: Completed
• Conditions: Peripheral Artery Disease
• Intervention / Treatment: Other: Ivus (Intravascular Ultrasound) of Amputation Specimens; Procedure: IVUS (Intravascular Ultrasound)

Detailed Description

Advances in the pathophysiology of Peripheral Arterial Disease (PAD) have been limited by the inaccessibility of the blood vessels to precise diagnostic interrogation. Traditional methods for studying disease in the peripheral arterial blood vessels have significant limitations. The development and refinement of IVUS (Intravascular Ultrasound) has provided a powerful in vivo method to assess plaque morphology. The potential of IVUS to quantify the structure and geometry of normal and atherosclerotic peripheral arteries will allow one to characterize specific lesions and to distinguish which plaques will or will not lead to complications.

Three primary hypotheses will be tested in this study: (1) IVUS combined with advanced digital image and signal processing provides a sensitive method to determine plaque geometry and composition in the human peripheral artery wall; (2) IVUS can discern specific arterial wall morphology, providing data that can be used to identify plaques that predispose the patient to late complications; and (3) IVUS-derived plaque structure can be used to predict responders and non-responders to pharmacologic therapy and percutaneous endovascular interventions.

These hypotheses will be tested as follows: (1) custom engineered IVUS analysis software will be used to describe the geometry, composition, and spatial component relationships of the vessel, (2) the morphology of lower extremity arterial plaque, as determined by IVUS, will be correlated with baseline clinical characteristics of subjects, and (3) the effects on plaque morphology after long term treatment with antihyperlipidemics will be determined.

There are three arms of the trial. (1) IVUS of Amputation Specimens: Histological sections of fresh arterial segments from amputation specimens will be correlated with IVUS derived radiofrequency data to quantify arterial plaque burden and composition (dense calcium, fibrous, fibro-fatty, and necrotic core components). (2)Observational Study: Patients undergoing standard lower extremity angiography for PAD will be studied with IVUS at the same sitting. IVUS finding will be correlated with demographic factors (age, gender, and race) and symptom severity (claudication, rest pain, tissue loss). Patients will be followed up for up to five years, and the occurrence of ischemic events (worsening of leg ischemia, need for intervention and re-intervention, and distant complications such as MI and stroke) will be reconciled with the arterial wall at the baseline examination. (3) Randomized Clinical Trial: A randomized, double-blinded clinical trial of high-dose atorvastatin vs. low dose atorvastatin will be performed in patients with intermittent claudication, based on our hypothesis with statin therapy will result in stabilization or regression of lower extremity arterial plaque, differences best assessed with high resolution imaging studies. Enrollment goals were not met due to treatment paradigm that has shifted to aggressive LDL control, therefore the overwhelming majority of patients were excluded due their existing statin therapy. On 6/25/08 the protocol and informed consent were amended to reflect elimination of the Randomized arm of this study and the restructuring of this arm to a Cohort Observational arm, correlating patients' current statin dosages with LDL levels and plaque morphology. This is the current design for this arm.

• Study Type: Observational
• Enrollment (Actual): 143

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44067
      • Cleveland Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with PAD undergoing standard lower extremity angiography.

Description

Inclusion Criteria:

1. Age ≥18 years.
2. Symptoms of intermittent claudication, rest pain, or minor tissue loss (Rutherford Category I - V).99
3. Non invasive laboratory evidence of peripheral vascular disease.
4. Angiographic demonstration of a 100 mm patent segment of a lower extremity artery containing at least one visually estimated stenosis of 20 - 80% diameter reduction.

Exclusion Criteria:

1. Acute limb ischemia, defined by a significant change in symptoms (one category on the Rutherford scale99 within the previous 14 days).
2. Concurrent oral anticoagulant therapy that cannot be safely withheld.

3. Extensive tissue loss and/or gangrene which would result in an above knee or below knee amputation(s).

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Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Arm I: In Vitro IVUS Plaque studies; IVUS of Amputation Specimens	Other: Ivus (Intravascular Ultrasound) of Amputation Specimens; Human lower extremity arterial segments will be obtained at autopsy and from amputation specimens. All imaging studies and vessel fixation will be undertaken immediately upon vessel procurement; in most cases this will occur within 2 hours of dissection and within 24 hours of death. The ex vivo portion of the study will make use of 150 excised vessels obtained over a 48-month period from randomly selected autopsy cases. From these vessels we expect to collect data from a minimum of 560 plaques
Arm 2: Obserational Study; IVUS for patients undergoing standard lower extremity angiography for PAD.	Procedure: IVUS (Intravascular Ultrasound); Standard diagnostic arteriographic images will be obtained. Appropriate oblique views will be acquired at the common femoral bifurcation. Next, IVUS will be performed obtaining ultrasound data from a 10 cm lower extremity artery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Develop automated algorithms to determine plaque geometry and composition from IVUS "backscattered" data	Spectral analysis of plaque	within 24 hours of amputation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Correlation: Plaque Structure and Composition	IVUS concurrent with angiography	During angiography for PAD

Collaborators and Investigators

• Sponsor: The Cleveland Clinic
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Matthew Eagleton, MD, The Cleveland Clinic

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2003
• Primary Completion (Actual): November 1, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: December 19, 2007
• First Submitted That Met QC Criteria: December 20, 2007
• First Posted (Estimate): December 21, 2007

Study Record Updates

• Last Update Posted (Estimate): February 8, 2017
• Last Update Submitted That Met QC Criteria: February 6, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: PAD; Peripheral Artery Disease; IVUS; Plaque
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis; Peripheral Vascular Diseases; Peripheral Arterial Disease
• Other Study ID Numbers: 6723; 5R01HL075721-05 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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