Effectiveness of Intensive Lipid Modification Medication in Preventing the Progression of Peripheral Arterial Disease (The ELIMIT Study)

Phase 4

Completed

Conditions: Peripheral Arterial Disease

Interventions: Drug: Ezetimibe
Drug: Niaspan
Drug: Statin therapy
Behavioral: Standard care
Drug: Aspirin
Drug: Placebo Niaspan
Drug: Placebo Ezetimibe
Drug: Clopidogrel
Procedure: Percutaneous transluminal angioplasty (PTA)

Registration Number: NCT00687076

Lead Sponsor: Baylor College of Medicine

Brief Summary: Peripheral arterial disease (PAD) occurs when arteries become narrowed or hardened because of a build-up of plaque or fat deposits. PAD develops most often in arteries in the legs, which can result in reduced blood flow to the legs and feet, occasionally causing leg pain and fatigue. Early identification of PAD and treatment with lifestyle changes or medications can help to keep legs healthy and lower risk for heart attack and stroke, but endovascular or surgical procedures may be necessary for people with severe PAD. Even after endovascular intervention, PAD symptoms must be continually monitored to prevent the development and progression of blockages in the arteries. The best approach for monitoring symptoms is still undetermined. This study will compare the effectiveness of an intensive combination of lipid modifying medications versus standard lipid modifying medications in treating people with significant PAD who have had an endovascular intervention.

Detailed Description: PAD occurring in the legs is a serious disease that affects about 8 million people in the United States. A person's risk for PAD increases with age but can also be raised by smoking or having diabetes, high blood pressure, high cholesterol, or heart disease. Symptoms of PAD may include leg cramps or pain while walking, foot pain while resting, and skin wounds or ulcers on feet and toes. However, because only about one in three people with PAD knows to seek treatment for these symptoms, many end up with advanced disease that requires significant medical intervention, such as an endovascular or other surgical procedure to open the blocked arteries. While these procedures are helpful in treating people with severe PAD, lifestyle modifications and certain medications are also needed for long-term management of PAD and improved quality of life. An intensive combination of lipid modifying medications may be superior to standard lipid modifying medications in reducing PAD-associated risk factors and improving overall health in people with PAD. This study will compare the effectiveness of an intensive combination of lipid modifying medications versus standard lipid modifying medications in preventing blockages and re-narrowing of arteries in people with significant PAD who have had an endovascular intervention.

Participation in this study will last a minimum of 2 years and a maximum of 5 years. All participants will first undergo baseline assessments that will include a medical history, vascular and physical exam, electrocardiograph (EKG), magnetic resonance imaging (MRI) scan, 3D ultrasound, blood pressure measurement test in the legs, treadmill walking distance test, urine test, blood draw, and questionnaires. A portion of the blood draw will be used for DNA analysis and genetic testing.

Participants who have not had an endovascular intervention in the 3 months before study entry will undergo a standard of care percutaneous transluminal angioplasty (PTA) procedure. First these, participants will complete a series of clinical review assessments that will include a review of social, vascular, and clinical history. Next, they will undergo the PTA procedure, which will involve the inflation and deflation of a small balloon in the area of the blocked artery. Additionally, participants may have a metal mesh tube called a stent placed in the blocked area, if deemed necessary by their physicians.

All participants will then be assigned randomly to receive standard care plus an intensive combination of lipid modifying medications (Simvastatin, Plavix, aspirin, Ezetimibe, and Niaspan) or standard lipid modifying medications with placebo (Simvastatin, Plavix, aspirin, placebo Ezetimibe, and placebo Niaspan). Participants will take their assigned medications daily for 24 months. Follow-up visits will occur at Day 10; Week 6; and Months, 6, 12, and 24 after beginning the study medications. During follow-up visits, participants will repeat the baseline assessments and the clinical review assessments from the pre-PTA visit. The Week 6 follow-up visit will include only a blood draw, questionnaires, and the clinical review assessments. Participants will also be contacted by phone to check their status every 2 to 3 months during treatment and every 6 months after treatment for up to 3 years.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 102

Inclusion Criteria

Symptoms consistent with calf claudication and described as life style limiting
Objective evidence of peripheral artery disease (PAD): Ankle brachial index less than 0.9 OR other hemodynamic or imaging modalities confirming significant PAD
Baseline imaging reveals superficial femoral artery (SFA) disease starting at least 5 cm from the origin of the SFA
Agrees to be available for follow-up and is able to participate in all study testing procedures
Weight and/or body characteristics that will allow testing with MRI
No known contraindication to lipid lowering agents
Serum creatinine level less than 2.5 mg/dL
Scheduled to undergo or has already undergone an endovascular intervention of a de novo lesion in the SFA with an anticipated result that would satisfy hemodynamic stability OR is medically managed and does not require an intervention at this time
Compressible arteries (if not, has toe brachial index [TBI] less than 0.7)
Has/had an A, B, C lesion amendable to a catheter based therapy (prior bypass is acceptable)

Exclusion Criteria

Non-atherosclerotic disease that is responsible for claudication
Unstable cardiac disease (e.g., unstable angina, heart attack within the 30 days before study entry, uncontrolled coronary heart failure, poorly controlled hypertension [systolic blood pressure greater than 180 mmHg and/or diastolic blood pressure greater than 100 mmHg], ventricular arrhythmias)
Pancreatitis
Documented hypercoagulable state
Clinically severe diabetic neuropathy
Rest pain, gangrene, or tissue loss
Active peptic ulcer disease or a recent gastrointestinal bleed that would prohibit the use of an anti-platelet (aspirin/Plavix)
Untreated or unsuccessfully controlled psychiatric disease
Chronic hepatic disease determined by aspartate transaminase (AST) and/or alanine transaminase (ALT) more than 3 times upper limit of normal (ULN) and/or total bilirubin more than 2 times ULN
Creatine phosphokinase (CPK) more than 3 times ULN (may be repeated once before patient is excluded)
Active gout symptoms or a uric acid level greater than 1.3 times ULN
Untreated hypothyroidism
Allergy to Plavix, nickel, titanium, niacin, Ezetimibe, statins, or their derivatives
Participated in another interventional study within the 30 days before study entry
Scheduled to undergo planned synchronous bilateral percutaneous transluminal angioplasty (PTA) procedures
Requires an above the ankle amputation
Scheduled to undergo elective surgery within 30 days after the PTA procedure
Has an implanted pacemaker, defibrillator, neural stimulator, brain clip, insulin pump, cochlear implant, or any other predetermined radiographic finding that would exclude MRI testing
Has claustrophobia that would prevent MRI testing
Recent drug or alcohol abuse history (less than 6 months before study entry) or is currently using or abusing excessive alcohol or drugs (excessive alcohol will be defined as greater than 14 drinks per week)
Past recipient of a cardiac, kidney, liver, lung, or other organ transplant (skin grafts are acceptable)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
1	Standard care	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
2	Standard care	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
1	Aspirin	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
2	Placebo Ezetimibe	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
1	Statin therapy	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
2	Statin therapy	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
1	Percutaneous transluminal angioplasty (PTA)	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
2	Placebo Niaspan	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
2	Percutaneous transluminal angioplasty (PTA)	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
2	Aspirin	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.
1	Ezetimibe	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
1	Clopidogrel	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
1	Niaspan	Participants will receive standard of medical care and treatment with intensive lipid modification using a statin plus Ezetimibe and Niaspan.
2	Clopidogrel	Participants will receive standard of medical care and treatment with standard lipid modifying medications plus placebo Ezetimibe and placebo Niaspan.

Primary Outcome Measures

Name	Time	Method
Effect of Intensive Lipid Modification Medication Therapy on Progression of Atherosclerosis and Restenosis of Femoral Arteries Measured Using High Resolution Magnetic Resonance Imaging (MRI) to Examine the Femoral Artery for Progression of Atherosclerosis	Measured at baseline and 24 Months	The primary outcome variable was the change in superficial femoral artery (SFA) wall volume over 24-months, as determined by MRI. The 24-month changes in SFA lumen and SFA total vessel volumes were also analyzed. Analysis details: A total of 102 patients were randomized. 87 patients completed baseline MRI. Between randomization and the baseline visit, 1 patient withdrew from the study, 8 patients opted out from baseline imaging, and 6 additional patients declined blood collection at baseline. The multilevel models (primary endpoint) used all available imaging data (n=91), including patients who only completed baseline imaging (n=20) or completed at least 2 imaging visits other than baseline (n=4).

Secondary Outcome Measures

Name	Time	Method
Change in Total Cholesterol (mg/dl) From Baseline to Month 12	Measured at baseline and 12 months	Lipids: Total cholesterol (mg/dl); Lipid Data at 12-Months (change from baseline) \[mg/dl\].