Randomized Trial of Imaging Versus Risk Factor-Based Therapy for Plaque Regression
Randomized Trial of Imaging Versus Risk Factor-Based Therapy for Plaque Regression
Background:

 - Atherosclerosis (thickening of the artery walls caused by cholesterol and other deposits)
 commonly occurs in the heart vessels and carotid (neck) arteries of adults. This is often
 present in individuals with high cholesterol levels in their blood. These patients are
 usually treated with cholesterol lowering medication ( statins ) along with modification of
 diet and exercise. Researchers are interested in investigating new approaches including
 magnetic resonance imaging (MRI) and computed tomography (CT) imaging studies to detect blood
 vessel blockages that would not otherwise be detected by cholesterol levels and risk factors
 for heart disease.

 Objectives:

 - To measure atherosclerosis in the heart vessels and carotid arteries using imaging tests
 (computed tomography (CT) and magnetic resonance imaging (MRI)) before and after standard
 treatment with cholesterol lowering medication ( statins )

 Eligibility:

 - Healthy individuals at least 55 years of age who are candidates for therapy to lower their
 blood cholesterol levels.

 Design:

 -  This study will involve one screening visit and seven study visits over a period of 2
 years.

 -  Participants will be screened with a physical examination and medical history, as well
 as blood samples and tests to ensure that it is safe for them to have CT and MRI scans.
 Participants will provide information on current medications, dietary habits, smoking
 status, alcohol and caffeine intake, and their level of physical activity.

 -  Participants will be divided into two groups. One group will receive standard doses of
 medication to lower cholesterol according to current treatment guidelines, while the
 other group will have MRI scans of the carotid arteries and a CT scan of the heart to
 determine the best medication dose levels.

 -  Visits 3 to 5 will be scheduled 3, 6, and 9 months after visit 2. During these visits,
 researchers will monitor for possible side effects and may change or adjust medications
 and doses.

 -  At visit 6, participants will have an MRI scan of the carotid arteries, a physical
 examination, and blood tests. Medications may be changed or adjusted.

 -  At visit 7, participants will have blood tests, and medications may be changed or
 adjusted.

 -  At the final visit, participants will have MRI and CT scans of the carotid arteries and
 heart, respectively, as well as a final physical examination and blood tests.
The overall aim of this proposal is to compare the effectiveness of an image guided approach
 to lipid lowering to standard therapy guided by clinical risk factors and blood lipid levels.
 Men and women over age 55 who are candidates for statin therapy will be randomized to usual
 cholesterol lowering care, or to care guided by MRI images of the carotid arteries.
 Participants randomized to the second, imaging guided, group will be assigned to LDL
 cholesterol targets according to the degree of atherosclerosis seen by MRI. The study
 endpoints will be the total degree of plaque regression seen, the dosage of statin drugs
 required to achieve that reduction, and the rate of cardiovascular events.

 FDG-PET is hypothesized to enable visualization of anti-inflammatory effects of statins that
 most likely occur before anatomic regression of the plaques can be demonstrated on MRI. A
 pilot substudy is to be conducted to explore this relationship. A subgroup of patients
 participating in the main study will be asked to participate in FDG PET imaging. The purpose
 of this pilot study is to determine if FDG avid lesions undergo a greater degree of
 morphologic regression with therapy controlling for the reduction in LDL cholesterol and the
 dosage of statins required to achieve that target.

 Although contrast-enhanced coronary CT angiography (CTA) with multidetector computed
 tomography (MDCT) has been used extensively to characterize coronary artery plaque
 composition, there is little data regarding its reproducibility. A recent study demonstrated
 excellent reproducibility for this technique but this study was performed using the older 64
 detector row CT scanners2. A pilot substudy will be conducted to study the reproducibility of
 coronary CT angiography using the newer generation of 320 detector row CT scanners.
-  INCLUSION CRITERIA:

 A. Men and Women greater than or equal to 55 years of age

 B. Candidates for lipid lowering therapy under NCEP ATP III guidelines without
 contraindication to statin therapy

 C. Willing to modify therapy to enroll in the study

 D. Willing to travel to the NIH for follow-up visits.

 E. Able to understand and sign informed consent

 F. Lab Eligibility parameters:

 -  eGFR > 45 mL/min/m2

 -  For age >60 test GFR within 1 week prior to contrast; For age less than or equal to 60
 test within 4 weeks

 INCLUSION CRITERIA FOR THE PET SUBSTUDY:

 Participants who are not participating in the CT Reproducibility study are eligible.

 INCLUSION CRITERIA FOR THE REPRODUCIBILITY SUBSTUDY:

 Patients will be selected who had a one RR interval initial CT scan with less that 10.5 mSv
 estimated radiation dosage and who will not be participating in the PET Substudy.

 EXCLUSION CRITERIA:

 A. Ineligibility for MR imaging due to:

 -  Previous pacemaker implantation

 -  Automatic implantable cardioverter-defibrillator (AICD)

 -  Metal implants or other ferromagnetic devices, or

 -  Foreign material

 B. Claustrophobia

 C. Contra-indication or allergy to statin medications.

 D. Current statin therapy at or above the maximum dosage permitted per study protocol.

 E. Use of fibrates, ezetimibe, niacin, or bile acid binding agents within 6 months of
 screening visit.

 F. Pregnancy and nursing.

 G. Liver failure defined clinically and by laboratory data.

 H. Mental, neurologic or social condition preventing understanding of the rationale,
 procedures, risks and potential benefits associated with the trial.

 I. Any other conditions that precludes safety for MRI and/or CT imaging per the researcher
 s evaluation.

 EXCLUSION FOR PARTICIPATION FOR GADOLINUIM CONTRAST. PARTICIPANTS MAY STILL UNDERGO ALL
 OTHER STUDY EVALUATIONS.

 (Inclusive of the above exclusion criteria):

 1. Allergy to gadolinium for scans using contrast; will be eligible for non-contrast
 scans.

 2. Acute renal failure, renal transplant, dialysis and renal failure (eGFR < 45 mL/min/m2
 and/or clinically diagnosed).

 3. Individuals with a history of liver transplant or severe liver disease.<TAB>

 4. Individuals with hemoglobinopathies or severe asthma.

 EXCLUSION FOR PARTICIPATION FOR IODINATED CONTRAST. PARTICIPANTS MAY STILL UNDERGO ALL
 OTHER SUDY EVALUATIONS.

 Prior hypersensitivity reaction to iodinated contrast injection, renal dysfunction (defined
 as eGFR < 45 mL/min/ m2) or a current clinical diagnosis of renal failure.

 EXCLUSION CRITERIA FOR THE PET SUBSTUDY:

 Patients who are unable or unwilling to comply with the physical activity restrictions or
 fast for 12 hours prior to FDG PET scanning will be excluded. Due to the need for dietary
 manipulation and the maintenance of strict glycemic control we will exclude diabetic
 patients from our initial study sample. Blood glucose measurements before injection must be
 within normal limits, less than 200 mg/dL (11 mmol/L).

 EXCLUSION CRITERIA FOR THE REPRODUCIBILITY

 Patients who did not have a one RR interval initial CT scan. Patients who will participate
 in the PET Substudy.