Clinical trial NCT01212900
Conditions: Atherosclerosis Hypercholesterolemia
Keywords: Atherosclerosis Cardiovascular Disease Cardiac MRI Cardiac CT Cholesterol
Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
Start date: 2010-09-30; Completion date: 2017-02-22
Enrollment: 230 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Lipid targets assigned according to the severity of atherosclerotic plaque measured as wall volume in the common and internal carotid arteries by MRI arm 2: Standardized statin therapy based on NCEP ATP IIIR guidelines, including clinical risk factors and blood lipid levels.
Interventions: intervention 1: Statins, HMG CoA
Intervention descriptions: intervention 1: Statin therapy

Protocol documents:
Prot_SAP_000.pdf: 
 
 
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1 
Short Title: Imaging Guided Lipid Therapy 
CC number: 
10-CC-0214 
Amended: 
  10/26/17 
PROTOCOL TITLE  
The RIGHT study: Risk stratification with Image Guidance of 
HMG coa reductase inhibitor Therapy 
 
Principal Investigator: 
 
 
 
 
 
  
Nehal Mehta, MD. 1 
E-mail:Nehal.Mehta@nih.gov 
 
 
 
  
 
Statistician:  
 
 
Colin, Wu, PhD1 
Office of Biostatistics Research, NHLBI 
E-mail: wuc@nhlbi.nih.gov 
 
Associate Investigators: 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Veit Sandfort, M.D 1  3 
Email: Veit.sandfort@nih.gov 
Email: Veit.Sandfort@gunet.georgetown.edu   
 
 David Bluemke, MD 2  Email: 
DBluemke@rsna.org 
 
Mark Ahlman, M.D. 1 
E-mail: Mark.Ahlman@nih.gov 
 
Alan Remaley, M.D1 
E-mail: alan.remaley@cc.nih.gov 
 
Tracy Cropper, R.N. 1 
E-mail: tcropper@mail.nih.gov 
 
 
 
Research Coordinator/Contact: 
 
Tracy Cropper, R.N. 1 
E-mail: tcropper@mail.nih.gov 
 


 
 
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1  Radiology & Imaging Sciences 
NIH Clinical Center 
Building 10, Room 1C351 
Bethesda, MD  
(301) 496-9491 
2 Extramural staff: 
  
University of Wisconsin  
School of Medicine & Public Health   
 
  
 
 
3. Extramural staff: 
Georgetown University  
School of Medicine 
3900 Reservoir Rd NW 
Washington, DC 2007 
 
 
 
 
 
Accrual number:  300 
Sponsor:  No 
Project uses Ionizing Radiation: Yes  
IND/IDE: No 
Project uses Durable Power of Attorney: No 
Off-site study:  No 
Multi-institutional protocol:  No 


 
 
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Table of contents: 
PROTOCOL TITLE ............................................................................................... 1 
Précis .................................................................................................................... 4 
1.0 
Introduction ................................................................................................ 4 
1.1  
Study Objectives: .................................................................................... 4 
1.2 
Background and Rationale ..................................................................... 5 
1.3 
Design .................................................................................................... 7 
2.0 
Eligibility Assessment and Enrollment ...................................................... 17 
2.1 
Inclusion Criteria ................................................................................... 17 
2.2  
Exclusion Criteria .................................................................................. 17 
2.3 
Screening Evaluation ............................................................................ 19 
2.4 
Registration Procedures ....................................................................... 20 
2.5 
Randomization Procedures .................................................................. 20 
3.0 
Subjects Implementation .......................................................................... 20 
3.1 
Study Design ........................................................................................ 20 
3.2 
Protocol Evaluation/Study Calendar ..................................................... 21 
3.3 
Concurrent Therapies ........................................................................... 22 
3.4 
Criteria for removal from Treatment/Protocol ........................................ 23 
4.0 
Supportive Care ....................................................................................... 23 
5.0 
Data Collection and Evaluation ................................................................ 24 
5.1 
Data Collection ..................................................................................... 24 
5.2 
Response Criteria ................................................................................. 24 
5.3 
Toxicity Criteria ..................................................................................... 24 
6.0 
Statistical Section ..................................................................................... 25 
7.0 
Human Subject Protection........................................................................ 28 
7.1 
Rationale for Subject Selection ............................................................. 28 
7.2 
Participation of Children: ....................................................................... 29 
7.3 
Evaluation of Benefits and Risks/Discomforts: ..................................... 30 
7.4 
Risks/Benefits Analysis......................................................................... 32 
7.5 
Consent and Assent Process and Documentation ............................... 32 
7.6 
Data Safety and Monitoring .................................................................. 33 
8.0 
Safety Reporting Requirements: .............................................................. 34 
8.1 
Adverse Event Definition ...................................................................... 34 
8.2 
IRB Adverse Event Reporting Guidelines: ............................................ 36 
8.3 
IND/IDE: ............................................................................................... 36 
9.0 
Multi-Institutional Guidelines: N/A ............................................................ 36 
10.0 Pharmaceutical and/or Investigational Device Information ....................... 36 
11.0 Reference: ................................................................................................ 42 
Appendices: ........................................................................................................ 46 


 
 
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Précis 
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.1  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. 
1.0 Introduction 
1.1  
Study Objectives: 
The purpose of this study is to evaluate the hypothesis that use of 
atherosclerosis imaging to set targets for cholesterol lowering therapy will 
result in greater regression of atherosclerosis than standard therapy.  
 
The primary efficacy endpoint of this study is the wall volume of the 
internal carotid arteries as measured by magnetic resonance imaging.   
 
Secondary endpoints are  
A. Arterial stenosis and plaque volume  measured by coronary MDCTA  
B. Dosage of statin medications required to achieve LDL targets.   
C. Combined incidence of stroke, nonfatal MI, myocardial 
revascularization, hospitalization for unstable angina or heart failure 
and death. 
D. FDG plaque uptake within the carotid and coronary arteries. 


 
 
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E. Reproducibility of arterial stenosis and plaque volume measured by 
MDCTA. 
1.2 
Background and Rationale 
 
The overall aim of this proposal is to compare the efficacy of an image 
guided lipid lowering strategy, with that of the standard lipid lowering 
approach i.e., guided by clinical risk factors and blood lipid levels.   
 
  The clinical efficacy of lipid modifying therapy to reduce cardiovascular 
(CV) endpoints has been demonstrated in multiple trials. Current 
recommendations for the initiation and titration of lipid therapy rely on 
evaluation of clinical and laboratory markers to estimate risk.  
Approximately half of patients with cardiovascular disease present with 
sudden death as their first indication of underlying atherosclerosis.  Most 
patients who suffer a first heart attack fall into a “low risk” categorization 
by commonly used risk scores.  Although cardiovascular disease is the 
most common cause of death in women, it is virtually impossible for 
women to reach the level of intermediate or high risk by current risk scores 
unless they are diabetic or over 70 years of age.3 Therefore, the 
effectiveness of current guidelines for  estimation of cardiac risk remain in  
question.   Better approaches to focus aggressive lipid modification 
strategies are needed in order to reduce the incidence of adverse events 
in lower risk individuals, and to ensure that patients at the greatest risk 
receive the most intensive available therapies.   Use of noninvasive 
imaging to determine atherosclerotic burden is a promising strategy to 
achieve the end of tailoring risk modifying therapy to those most at risk.   
 
  Previous studies including our own have demonstrated the ability of lipid-
modifying drugs, specifically HMG-CoA reductase inhibitors, to induce 
measurable regression of atherosclerosis. We propose to compare two 
different approaches to achieve atherosclerotic plaque regression and 
stabilization using the primary endpoints of carotid atherosclerotic plaque 
volume and composition defined by MRI. We also propose to measure 
coronary plaque regression defined by 320 detector row CT angiography, 
in order to evaluate whether carotid and coronary plaque regression occur 
in parallel.  Finally, we propose to compare the benefit of these two lipid 
lowering strategies on clinical CV events.  In order to achieve all of these 
objectives, state-of-the-art MRI techniques refined from our previous trial 
in similar population will be employed to quantify atherosclerotic plaque 
volume and composition in the carotid arteries, and to measure carotid 
arterial distensibility and pulse wave velocity. The newest generation of 
320 detector CT scanners will be used to measure atheroma volume in 
the coronary arteries and differentiate between calcified and non-calcified 
lipid-rich and/or fibrous lesions.  We hypothesize that guidance of lipid 
modifying therapy using imaging assessment of atherosclerosis to 
intensify or reduce lipid lowering therapy in patients with respectively 
greater or lesser plaque volume at the baseline examination will result in 
greater plaque regression and stabilization than standard NCEP guided 
therapy with the same or superior safety and/or treatment adherence 
profiles.   
 
In a subset of individuals we plan to look at plaque inflammation using 
FDG PET.  Molecular imaging compliments traditional anatomical imaging 


 
 
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approaches that identify plaque structure and composition.   
 
It is widely postulated in the literature that 18F-fluorodeoxyglucose (FDG) 
imaging can improve risk assessment and prognostication through the 
identification of high-risk “vulnerable” plaques, plaques that demonstrate 
heightened inflammation, neovascularization or apoptosis.  The primary 
target is the carotid and coronary arteries, imaging will also include the 
ascending and descending aorta, and the iliac arteries.  Successful FDG 
PET imaging has been performed in large vascular beds, including the 
carotid arteries, and recent preliminary reports suggest the potential for 
noninvasive coronary plaque imaging.  The advantage of nuclear imaging 
is that multiple vascular beds can be imaged with a single radionuclear 
isotope administration. 
  
In a subset of 60 individuals we plan to study the reproducibility of arterial 
stenosis and plaque volume as measured by MDCTA.  
 
At present, there is no available data on the reproducibility of 320 detector 
row MDCT for measuring arterial stenosis and plaque volume.  This data 
will allow investigators to determine whether measured changes in 
stenoses and plaque morphology exceed that expected from the limits of 
measurement error in CTA and thus make the results of ongoing trials 
more reliable.  
 
 
Consistent with such objectives, our specific aims are: 
 
1st Aim 
To examine whether image guided lipid lowering therapy is superior to 
NCEP guided therapy in promoting carotid atherosclerotic plaque 
regression and stabilization.   
 
2rd Aim 
To investigate whether the observed change in carotid atherosclerosis 
volume measured by MR, parallels observed change in coronary 
atherosclerosis volume measured by MDCT angiography.  
 
3rd Aim 
To examine whether MRI guided plaque regression and stabilization 
produces greater reduction in clinical CV events than standard NCEP guided 
therapy.  
 
 
4th Aim  
To examine the statin dosages required to promote plaque regression and 
stabilization differ between conventional and image guided strategies.   
 
5th Aim 
To investigate whether FDG PET activity predicts carotid morphological 
plaque regression and stabilization in both the carotid and coronary 
arteries and compare the efficacy of PET based prediction with MRI.  


 
 
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6th Aim 
To correlate FDG uptake in the carotid, coronary, aortic, and iliac arteries 
with absolute values and changes in hematological biomarkers of vascular 
inflammation, thrombosis and atheroprotection at and between each time 
point. 
 
7th Aim 
To explore the variability of FDG uptake within willing individuals who are 
participating in the main study.  
 
8th Aim 
Reproducibility of arterial stenosis and plaque volume measured by 
MDCTA. 
 
Thus, for the purpose of accomplishing these aims, we propose to compare 
an imaging-guided lipid modification strategy with standard therapy in a 
randomized, controlled clinical trial.  The results of this trial will be directly 
applicable to improvement of strategies for plaque stabilization and 
prevention of atherosclerotic events.  
 
1.3 
Design 
 
Study design:  This is a randomized, controlled clinical trial in which 200 
men and women aged 55 and older will be randomized to one of two 
treatment arms.  The study duration will be 24 months.  The control group 
will receive standard care with NCEP ATP IIIR guided statin therapy as 
determined by clinical risk factors.  The imaging intervention group will 
have lipid targets assigned according to the severity of atherosclerotic 
plaque measured as wall volume in the common and internal carotid 
arteries by MRI.  Patients in the lowest tertile of carotid wall volume (using 
the MESA study as a reference population(4)) will have statin therapy 
adjusted to a target LDL between 100-130 mg/dL.  Patients in the middle 
tertile will receive statin therapy to an LDL target of 70-100 mg/dL.  
Patients in the highest tertile will receive statin therapy to achieve LDL-c 
levels below 70 mg/dL.  Participants will be randomized in a equal ratio 
into imaging guided and control groups, respectively.  This recruitment 
goal is designed to account for an estimated 20% attrition rate and 
maintain adequate power at the 24 month endpoint.  
 
 


 
 
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TreTreatment and Assessments 
 
At the initial study visit, all participants will undergo measurements of 
carotid arterial wall volume using contrast enhanced MR.  For participants 
randomized to the imaging intervention arm, measured wall volume will be 
compared against the MESA population, and treatment targets will be 
assigned according to the magnitude of plaque volume.  Participants with 
mild or no atherosclerosis, defined as the lowest tertile of wall volume, will 
have statin therapy adjusted to a target range of 100-130 mg/dL   
Participants in the middle tertile will receive statin therapy adjusted to 
achieve a target LDL 70-100 mg/dL.   Participants with the most severe 
atherosclerosis will receive statin therapy to an LDL target between 40 
and 70 mg/dL.  Participants in the control arm will have lipid sub-fraction 
targets determined according to estimated 10 year cardiovascular risk, as 
per standard NCEP guidelines.  
 
Allowable statin compounds and maximum dosages are: 
 
compound 
maximum allowable dose 
comments 
atorvastatin 
80 mg /day 
 
fluvastatin 
80 mg/ day 
 
lovastatin  
(immed. release) 
 
80mg/day 
 
Measure 
Method 
Location 
Frequency in the 
study 
Plaque thickness 
MRI – with and 
without contrast 
2 carotid sites 
Baseline, 12 and 24 
months 
 
Plaque area 
MRI – with and 
without contrast 
2 carotid sites  
Baseline, 12 and 24 
months 
 
Plaque volume 
MRI – with and 
without contrast 
2 carotid sites 
Baseline, 12 and 24 
months 
 
Fibrous/Lipid intra-
plaque ratio 
MRI – with and 
without contrast 
2 carotid sites 
Baseline, 12 and 24 
months 


 
 
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extended release 
60 mg/day 
pravastatin 
80 mg/ day 
either 40 mg immediate 
release twice daily OR 80 mg 
extended release once daily 
rosuvastatin 
40 mg/ day 
 
simvastatin 
80 mg/day 
 
 
Subjects assigned to both arms of the study will undergo carotid MR for 
plaque evaluation at baseline, 12 and 24 months of followup. 320 detector 
row MDCT angiography will be performed at baseline and 24 months. 
Only unscheduled visits for evaluation of drug toxicity or potential clinical 
events will not coincide with intervention visits. 
 
Carotid MRI 
 
Participants will undergo 2D and 3D carotid MRI using a 3 Tesla scanner 
and surface carotid coils. Baseline non-contrast carotid images will be 
acquired with dual 3 inch surface coils (phased array) positioned 
immediately below the angle of the mandible on each side of the neck. 
The protocol will be same as previously used in studies performed at the 
N.I.H. by Wasserman et al (5), adapted by Drs. Bluemke and Lima as part 
of the MESA carotid MR imaging protocol and used by Drs Sibley, Lima 
and Bluemke in the NIA Plaque study. (AHA Scientific Sessions 2009, 
manuscript under review) Initial images will be acquired as a three-
dimensional volume using a 3D variable flip angle TSE sequence 
(SPACE) at 0.8 mm3 isotropic resolution, in 64 partitions using GRAPPA 
with 2-fold acceleration.  This sequence will be T2 weighted with a 
TR=1300 ms and TE 123 ms.    The 3D volume data will be used to 
determine the course and orientation of the common and internal carotid 
arteries bilaterally, and to determine the location of the carotid flow divider 
(bifurcation).  This sequence will be used to guide placement of baseline 
non-contrast images covering two 2.4 cm arterial volumes on each side of 
the neck, selected to include the areas of maximal atherosclerotic 
involvement assessed as perpendicular plaque thickness. Targets will 
then be imaged cross-sectionally with a DIR fast spin echo pulse 
sequence, ECG gated, with black blood and fat suppression. Slice 
thickness will be 2.0 mm with in plane resolution of 500-600 microns. 
Images will be obtained with both short TE=5msec (PDW weighted 
images) and long TE=60msec (T2 weighted images) with inversion times 
adjusted to minimize blood pool signal (approximately 600 ms) and 
repetition times of one and two cardiac cycles (RR intervals). After 
contrast administration the same carotid targets will be re-imaged as 
described above. Inversion time will be reduced from 600 to 200 msec to 
account for the effect of circulating gadolinium contrast. 
 


 
 
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Data Analyses of Carotid MR imaging 
 
Co-investigators blinded to the results of treatment group assignment and 
patient characteristics will be responsible for the measurement of all  MR 
outcome variables, specifically lumen area, wall volume fibrous content 
and lipid core.  Measurements will be performed using commercially 
available semiautomatic contouring software (QPlaque, Medis Inc) 
workstation.  Vessel contours will be reviewed by an experienced MR 
physician. Measurements for the primary study endpoints will be obtained 
from the post-contrast enhanced sequences as these provide the best 
definition of the vessel wall and lipid core.(4)  T2 images will be used for 
confirmation of these measurements on the post-contrast series when 
necessary.  As previously reported, the lipid component of plaque is hypo-
intense on T2 images, while fibrous components are isodense (6-8). The 
primary study outcome variables will be measured from the 2-D carotid 
images and derived from these measurements of wall thickness in the 
radial direction.  The calculated area in each slice will be summed for the 
slices acquired of the relevant vessel, allowing volume calculation of wall 
and plaque components.  Identical measurements will be performed on 
the 3D sequences for purposes of calculating accuracy and agreement 
with the current standard 2D approach for use in future investigations.     
 
Coronary angiography by 320 detector row MDCT 
 
1)  Coronary calcium scan  
Will be performed using the following protocol: 
 
-No contrast. 
 
-CT Imaging:  tube voltage = 120kV, tube current = 140 mA, gantry 
rotation speed = 0.35 seconds, slice thickness = 0.5 mm, rows = 256-320, 
range = 128-160 mm.  X-ray tube will be on for a total of 0.35 seconds.  
Estimated radiation dose = 1.5 mSv. 
 
2)  Rest Coronary arterial imaging 
Coronary arterial imaging will be performed during a 4-5 ml/sec 
intravenous iodinated contrast (ISOVUE®-370) infusion using the following 
parameters:  If heart rate is < 66  bpm   prospective ECG gating at 70-80% 
of one R-R interval, X-ray exposure time ranges from  0.423 – 0.350 sec 
(depending on heart rate). If heart rate is ≥ 66  bpm   prospective ECG 
gating at 40-80% of two R-R intervals, X-ray exposure time ranges from  
1.174 sec – 0.714 sec (depending on heart rate) tube voltage = 120kV, 
tube current = 300 -580 mA depending on BMI and gender, gantry rotation 
speed = 0.35 or 0.375 seconds, slice thickness = 0.5 mm, rows = 256-320, 
range = 128-160 mm.  The automated bolus tracking feature will be used 
to judge contrast bolus arrival and optimize image quality. 
 
The estimated radiation dose for the entire cardiac computed protocol 
(Calcium scoring (1.5 mSv) + Coronary arterial imaging (3-9 mSv) is 4.5 
mSv to 10.5 mSv depending on patient heart rate, BMI, and gender.  Beta-
blockers will be used to control the heart rate and thus maintain the 
radiation dose as low as reasonably achievable.  Depending on patient 
size, a maximum of 2 ml/kg iodinated contrast will be used up to a 
maximum of 130 ml. 
 


 
 
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Beta Blockade 
 
In order to optimize image quality by reducing cardiac motion, participants 
will receive beta blockade on the day of the scan.  Participants will have 
heart rate and blood pressure measured, and will be assessed for 
contraindications to beta blockade (bradycardia, heart block, active 
wheezing, history of adverse reaction).   
 
 
Since the approach to pre-scan beta-blockade is unique to the individual 
participant, the supervising physician customizes the dose on an individual 
subject to achieve a goal heart rate of less than 60 beats per minute.  A net dose of 
metoprolol 25-200 mg or atenolol 50-100 mg or diltiazem 90-360 mg will be 
administered orally potentially in divided doses over a period of approximately 1-
2 hours titrated to achieve a heart rate less than 60 beats per minute.  In addition, 
metoprolol or diltiazem 5-30 mg intravenously may be administered in divided 
doses at the judgment of the supervising physician if heart rate is not adequately 
controlled and the subject appears capable of tolerating the additional 
medication.  Vital signs will be obtained and documented following metoprolol 
administration.  If at any time the heart rate is <50 bpm and/or the systolic BP is 
<100, the supervising physician will be notified.  All participants will be assessed 
ofr symptoms of bradycardia, hypotension and orthostasis after scan completion.  
 
 
Nitrate therapy 
 
The use of short acting nitrates (i.e. sublingual nitroglycerine) just prior to 
MDCT is required for patients with systolic blood pressure >110mmHg to 
allow for accurate assessment of the degree of coronary artery stenosis, 
reduce vasospasm and to standardize vasomotor tone.  Potential 
contraindications to nitroglycerine use should be reviewed prior to 
administration (known allergy or severe intolerance, critical aortic stenosis, 
pre-existing hypotension).  If the patient cannot receive nitroglycerine (due 
to intolerance, borderline blood pressure, investigator judgment), the 
patient may still proceed with the study. Known risks of nitroglycerine use 
include headache, reduction in blood pressure, hypotension.  
 
CT image analysis 
 
CT angiogram images will be reconstructed and post-processed on a 
separate workstation using Vitrea (Vital Images, Inc) software.  The 
coronary tree will be segmented for analysis using a 16 segment AHA 
model according to the CORE-64 protocol (9).  Vessels larger than 1.5 mm 
in luminal diameter will be analyzed.  The worst lesion per segment will be 
assessed.  Luminal stenosis will be measured using semi-automated 
software. The spatial volume contained within the visible external wall of 
the vessel and the volume of the vessel lumen will be measured. A 
standardized under-patient phantom will be included in each scan to 
permit between-scan correction of density measurements.   


 
 
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Informed written consent will be obtained for each participant. Exclusion 
criteria will include contraindications for CT imaging or contrast 
administration and arrhythmia. 
Coronary calcification 
Coronary calcification will be measured by the Agatston(10) method, 
correcting lesion area by the density of calcification in the lesion.  A 
density independent volume score will also be calculated.  Total coronary 
artery calcium scores will be generated by summing the values from the 
left main, left anterior descending, left circumflex and right coronary 
arteries.  Readers will be blinded to subject identity.   
Plaque quantification 
 
Raw data will be reconstructed at 0.5 mm slice-thickness by a multi-
segment reconstruction algorithm. The baseline axial MDCT images with 
adequate reconstruction phase will be post processed and analyzed by 
commercial software (Sure Plaque, Toshiba Medical Systems). Lumen 
and wall boundaries of target vessels will be semi-automatically detected 
on cross sectional images. Under the guide of stretched multiplanar 
reconstructed image (SPR), two experienced readers will review and edit 
lumen and outer wall contours of coronary segments of the left anterior 
descending coronary artery (LAD), left circumflex coronary artery (LCX) 
and right coronary artery (RCA) from ostium to vessel diameter > 2.0mm 
from cross sectional image by each 1.0 mm in length. Segments with 
artifact, blur, or stent will be excluded. Volume estimates are obtained by 
multiplying cross sectional area by slice thickness. Coronary wall volume 
is computed by subtracting lumen volume from vessel volume.  
 
To quantify coronary lumen volume, vessel wall volume, and total vessel 
volume by MDCTA we will obtain three indices from MDCTA analysis of 
the lumen and vessel borders: 1) coronary lumen volume/ vessel volume 
(LV/VV), 2) coronary wall volume/ vessel volume (WV/VV) and 3) coronary 
wall volume/ lumen volume (WV/LV) (Fig. 1). The greatest value for all 
indices obtained for each vessel and patient will be recorded.  
 
 
 
 
 
 
 
Outer contour  – volume circumscribed by the outer border of the vessel 
wall (mm3) 
Lumen  – volume circumscribed by the inner border of the vessel wall 
(mm3) 
 
LV 
 
VV 
Figure 1: 
T = wall thickness 
LV= lumen volume 
VV = vessel volume 


 
 
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Wall volume = Outer contour volume – lumen volume (mm3) 
 
 
PET Substudy 
 
A subgroup of 60 patients will be recruited to participate in PET scanning 
which will be performed twice, once at study initiation and after 6 months 
of trial-directed statin therapy.   
 
Information including cardiovascular risk factors and other medication, 
including anti-inflammatory drugs, use will be collected. The total 
cholesterol and LDL levels and the dosage of statins required to achieve 
that target will be recorded. 
 
Inclusion Criteria: 
Participants who are not participating in the CT Reproducibility study are 
eligible.  
 
Exclusion Criteria: 
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).  
 
Hematological Biomarkers Markers: 
Blood tests for inflammatory markers will be incorporated into the baseline 
and 6 month blood draws. Standard investigations will include C-reactive 
protein, matrix metalloproteinase -3 and -9, interleukin-18, cathepsin K, 
fibrinogen, adiponectin, and plasminogen activator.12-13 A tube of blood will 
be stored at -70oC for testing of further markers defined at a later date.  
 
FDG PET Preparation: 
Study subjects will be asked to fast for 12 hours prior to PET scan.  On the 
morning of the PET study, a low carbohydrate meal will be provided to 
study participants.  Patients will be asked to avoid exercise 24 hours prior 
to scanning.   
 
Carotid and Cardiac FDG PET Imaging Technique: 
On the morning of the scan, Metoprolol 50 – 100 mg PO will be 
administered to slow the heart rate and optimize the acquisition of 
diastole.1 
 
The dose of FDG administered, duration between FDG injection and PET 
image acquisition, and the method of quantification of FDG uptake will be 
standardized.15 The injected dose of 18F-fluorodeoxyglucose will be 5.2 
MBq/kg (140 mCi/kg) of lean body mass to a maximum of 12.5 mCi.  


 
 
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Patients will be kept resting comfortably in a semi-dark room.  Scanning 
will be initiated after 90 minutes.16-20 Typically, extended time imaging will 
be performed of the coronary and carotid beds first, followed by a 5 – 15 
minute break and imaging of the remainder of the body.  
 
The initial acquisition will centered over the heart in 3-dimensional mode 
for at least 20 minutes.  When feasible, both cardiac and respiratory gating 
will be performed.  Images will be acquired in list-mode allowing for both 
single phase and segmented reconstructions.   
 
Subjects will be placed in a head holder and mobility-restricted with 
padding and tape-reminders. Using ultrasound, performed prior to the 
FDG injection, the carotid bifurcation will be located and a single-bed 
position high-resolution carotid PET scan will be performed using 3D 
mode with a minimum acquisition time of 9 minutes.21  
 
After a short break, lasting 5 – 15 minutes, body PET scanning will be 
performed. Body imaging will use standard 3D mode techniques and will 
consist of sequential emission images obtained with 16 cm fields of view 
each acquired over at least a 2 minute interval. Scanning will extend from 
the skull base to mid-thigh obtained in the cranial-caudal direction.   
 
CT imaging or MRI is necessary for attenuation correction and signal 
localization. 
 
CT / MR Acquistion: 
All studies will be performed according to routine protocol using a 
dedicated PET/CT system, or when available, a dedicated MR/PET.  
These devices are comprised of a PET scanner coupled to either a 
multislice CT or MRI scanner.  With PET/CT, the PET and CT components 
are mounted back-to-back and mechanically calibrated to ensure 
alignment of the CT and PET planes; the imaging protocol consists of an 
initial CT acquisition followed by the PET study.  During 2011, the NIH is 
slated to receive the Siemens Biograph mMR (molecular MR) which is the 
first integrated MR/PET scanner; this state-of-the-art machine 
incorporates a ring of lutetium oxy-orthosilicate crystal PET detectors 
inside the bore of a 3T MRI magnet and allows for simultaneous MRI and 
PET acquisitions.  
 
CT or MRI scanning will be performed from skull base to mid-thighs using 
appropriate respiratory and cardiac gating.  CT parameters (Biograph, 
Siemens PET/CT) include a spiral acquisition using 120 kVp and 115 mA 
with a section thickness of 2.5 mm; no oral or intravenous contrast 
material will be administered for the CT.   The MR acquisition (Verio, 
Seimens) will employ the Total imaging matrix (Tim) coil technology using 


 
 
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15 
standard parameters with field of view and matrix size adjusted to the 
imaged body part. 
 
High Resolution Carotid MRA: 
In order to facilitate the comparison between MRI and PET imaging prior 
to the availability of the integrated MR/PET unit, an additional high 
resolution carotid MRA examination will be performed at the 6 month time 
point.  This gadolinium enhanced study will use the standard carotid MRA 
study protocol and be scheduled on the same day or within a 2 week 
interval from the PET scan.  Carotid positioning will be reproduced through 
positioning technique using careful measurement, such as the distance 
between the chin and sternal notch, and employing mobility-restricting 
equipment, like the head holder and tape reminders. 
 
Image Reconstruction and Registration of Carotid and Cardiac FDG PET 
Imaging: 
PET image reconstruction will use standard filters for a fully iterative 
process using optimized spectral content measure with at least 2 iterations 
and 28 subsets.  High resolution reconstruction of the neck will be 
performed using at least 256 x 256 matrices; other vascular beds will be 
reconstructed using at minimum the standard 128 x 128 matrices.  
 
Matching PET/CT and MR/PET images will be fused.11  Both vendor 
specific software and open source programs will be used for region of 
interest delineation for partial volume correction and for vessel wall and 
lumen for calculation of vessel wall FDG uptake.22 
 
Imaging of the thorax will be viewed as both summed and gated 
reconstructions. For the gated reconstruction, 8-frames per cardiac cycle 
will be binned and the usable frames from middle to late diastole that have 
minimal blurring will be extracted and summed to enhance count density 
of the coronary arteries and warped for co-registration with the diastolic 
and respiratory gated CT / MR data. 
 
Data Analyses of FDG PET Imaging: 
For each patient scan, quantitative analysis will be performed of carotid 
and coronary arteries, aortic arch, ascending and descending aorta, 
abdominal aorta and iliac vascular territories.  Arterial wall lesions with 
radioactivity concentrations above the mean blood-pool activity, and/or 
with calcification detected by CT and with morphology consistent with that 
of a plaque will be considered plaque and included in the assessment. CT 
/ MR evaluation will be performed to identify atherosclerotic plaque as 
abnormal wall thickening with or without the presence of other features, 
like a lipid core or focal calcification, on a segment by segment basis.   
 


 
 
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Maximum standardized uptake value (SUVmax) corrects for patient weight 
and injected dose-decay: 
 
SUVmax (g / ml) = maximum activity (Bq / ml) x weight (kg)   
                          (dose (Bq) x 1000 (g/kg)) 
 
Target (plaque) -to-background (blood) ratio (TBR) normalizes vessel wall 
FDG uptake to the circulating FDG concentration.  Once an region of 
interest (ROI) is defined, either an FDG avid plaque or an FDG negative 
area with plaque features identified on CT or MR, the TBR is derived from 
an mean signal within the ROI divided by the mean signal from a large 
adjacent vein, typically the jugular vein for the carotids and the inferior 
vena cava for the aorta and iliac vessels.   
 
The target-to-background ratio is calculated: 
 
TBR =           mean voxel value within ROI (MBq/ml) 
                              mean voxel value within jugular vein ROI (MBq/ml) 
 
MDCT Reproducibility Substudy 
A subgroup of 60 participants with CT angiography performed in a single 
R-R interval (scanning heart rate ≤64 bpm) and estimated radiation 
dosage under 10.5 mSV will return 4 weeks after a protocol scheduled CT 
for a second reproducibility CT scan. The reproducibility CT angiography 
will be performed according to the same methods as the baseline imaging 
(pg 10).  Coronary calcium scanning will be omitted to reduce radiation 
dosage, as the reproducibility of calcium scoring has been well studied.  
Participants in the reproducibility subset will undergo a total of three CT 
angiography studies over the 24 month study period.  The 10.5 mSv 
estimated dosage inclusion criterion will ensure that reproducibility 
patients do not cumulatively receive more than the currently consented 
radiation dosage limit.  In fact, for the reproducibility CT angiogram, scan 
parameters will be set to limit imaging to a single heartbeat regardless of 
patient heart rate or arrhythmias.  This will ensure that radiation exposure 
cannot exceed the 21 mSv consented limit for the combination of main 
protocol and reproducibility substudy angiograms in each study year.   
 
Sixteen to twenty-four patients (total, n=60) will be selected from three 
groups: (a) patients with a calcium score of 0-99, (b) patients with a 
calcium score 100-399 and (c) patients with a calcium score of > 400.  
These 60 scans will be interpreted by two readers, allowing assessment of 
both intra and interobserver variability as well as repeatability limits.   
 
Inclusion Criteria: 
Patients will be selected who had a one RR interval initial CT scan with 
less than 10.5 mSv estimated radiation dosage.   


 
 
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Exclusion Criteria: 
Patients who will participate in the PET substudy.   
 
The repeat CT scans will be performed using the same protocol as the 
initial CT scan.  The data obtained from the repeat CT scan will be 
analyzed in the same manner as that obtained during the initial scan.  
 
2.0 Eligibility Assessment and Enrollment 
2.1 
Inclusion Criteria 
A. Men and Women  > 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 <= 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 than 10.5 mSv estimated radiation dosage   
and who will not be participating in the PET Substudy.  
 
2.2  
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.   


 
 
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D. Current statin therapy at or above the maximum dosage permitted 
per study protocol (section 1.3,above).  
 
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 Gadolinium 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.  
4.  Individuals with hemoglobinopathies or severe asthma. 
 
Exclusion for participation for iodinated contrast:  Participants may 
still undergo all other study 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).  
 


 
 
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19 
Exclusion Criteria for the Reproducibility Substudy: 
Patients who did not have a one RR interval initial CT scan.  
Patients who will participate in the PET Substudy. 
 
2.3 
Screening Evaluation 
On- Study Assessments:   
 
Study activities below (see Appendix B for Flow Chart) specify the 
required study tests and procedures for participants.   
Baseline visit tests and procedures will be completed 2 weeks 
before the first dose of study medication, unless otherwise noted. 
At the baseline visit, the Investigator and/or study staff will:  
 
A. Review the study procedures and determine that the eligible 
patient is willing to comply with all protocol requirements;  
 
B. Review the inclusion and exclusion criteria with the patient and 
determine if the patient can be a participant in the study;  
 
C. Record previous and concomitant medications, including vitamin 
and herbal supplements for the 4 weeks before the first dose of 
study medication;  
 
D. Complete patient medical history and physical examination 
including vital signs, height, and weight; 
 
E. Collect blood and complete laboratory safety evaluations: 
 
 Complete blood count (CBC) with platelet and differential,  
 
 Chemistry Labs: Electrolyte Panel, Creatine, Billirubin 
(total), Aspartate Amino-Transferase (AST), Alanine 
Aminotransferase (ALT), Alkaline phosphatase (Alk 
Phos), Uric acid, Protein (total), Albumin, Calcium, 
Phosphorous, and Magnesium),  
 
 12 hour Fasting Cholesterol (Chol) tests: Chol Total, High 
density lipoprotein (HDL), Triglycerides, and calculated 
Low density lipoprotein (LDL) 
 
 Creatine kinase (CK) 
 
 High sensitivity C-Reactive Protein (CRP) 
 
 Urine pregnancy test (for women of childbearing age) 
 
 Additional 2 tubes of blood will be stored for possible 
additional testing (not to include genetic or DNA analysis)    
 
F. Review baseline carotid MRI study regarding feasibility of 
enrollment;  


 
 
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20 
 
G. NIH Pharmacy will randomize patients to protocol. 
 
H. CT angiography scan will be performed at baseline and at 24 
month endpoint. Reproducibility sub-study patients will have an 
additional CT angiography 4 weeks after either baseline or 24 
month scan.   
 
I. Carotid MRI 0, 12, 24 months both non-contrast and post 
gadolinium administration.  Total scan time will be 
approximately 1 hour.   
 
J. Scheduled study visits which are part of the trial expected 
procedures will be made by one of the Investigators including 
the Nurse Coordinator. Clinical follow up will be made at the 
time of one of  7 scheduled clinic visits or in response to 
notification of any perceived clinical alteration.  
 
Study Calendar – Appendix B 
2.4 
Registration Procedures 
Upon completion of the screening process, eligible subjects will be  
enrolled on the study and will begin treatment after being 
randomized by the NIH Pharmaceutical Development Services.  
2.5 
Randomization Procedures 
Eligible participants will be open-label randomized by the NIH 
Pharmaceutical Development Service in to either the image guided 
therapy arm or the standardized treatment arm using a random 
number table used by the NIH Pharmaceutical Development 
Service Department.  Double blinding is not feasible in light of the 
need for study physicians to titrate drugs to LDL targets.   
 
The treatment group assignments will be blinded to the MRI and CT 
readers.  If a participant should need to come off study for any 
reason, they will be informed which arm they were randomized to. 
 
3.0 Subjects Implementation 
3.1 
Study Design 
This is a randomized, controlled clinical trial in which 200 men and 
women aged 55 and older will be randomized to one of two 
treatment arms.  The study followup will be 24 months.  The control 
group will receive standard care with NCEP ATP IIIR guided statin 
therapy as determined by clinical risk factors.  


 
 
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The imaging intervention group will have lipid targets assigned 
according to the severity of atherosclerotic plaque measured as 
wall volume in the common and internal carotid arteries by MRI.  
Patients in the lowest tertile of carotid wall volume (using the MESA 
study as a reference population(4)) will have statin therapy adjusted 
to a target LDL between 100-130 mg/dL.  Patients in the middle 
tertile will receive statin therapy to an LDL target of 70-100 mg/dL.  
Patients in the highest tertile will receive statin therapy to achieve 
LDL-c levels between 40 and less than 70 mg/dL.  Participants will 
be randomized in equal numbers to the two study arms.   
 
We estimate we will accrue approximately 3-4 subjects a month, 
leading to full accrual within 50 months. 
3.2 
Protocol Evaluation/Study Calendar 
Treatment Arms: Randomized 1 (Arm A):1 (Arm B) 
 
A. Statin therapy with lipid targets determined by plaque imaging.  
 
1. Lowest tertile of plaque volume:  
 
LDL 100-130 mg/dL achieved with statin therapy 
2. Middle tertile:   
 
LDL 70-100 mg/dL achieved with statin therapy 
3. Highest tertile:   
 
LDL below 70 achieved with statin therapy 
 
B.  Standard lipid therapy as determined by NCEP guidelines 
 
Protocol Evaluation 
 
A. Main Study Subjects will have a total of  7 visits (Screen plus 
follow up visits).  PET sub-study subjects will have an additional 
1-3 visits. Reproducibility sub-study subjects will have a single 
additional visit.  Visits 2 will follow the Protocol Evaluation 
schema in Appendix B. Visits will occur within +/-  30 days due 
for unforeseen events.  
 
B. Safety Measures (each visit, starting with week 0): 
 Safety labs: Hepatic panel (Alk Phos, ALT, AST, Bilirubin 
(total & direct) and creatine kinase measured during the 
course of the study. Urine HCG test for women of 
childbearing age.  Blood glucose measurements prior to 
PET imaging. 
 Review of interim medical history and evaluation for 
interim adverse events, off treatment or off study criteria. 


 
 
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22 
Complete review and recording of participant medications 
including over the counter and herbal compounds.   
 
 Prior to CT and MRI scanning:  Obtain MRI Screening 
Questionnaire (MRI scan days only) and estimated 
glomerular filtration rate (eGFR) the day of receiving 
iodinated contrast or gadolinium based contrast.  Urine 
HCG test for women of childbearing age.   
 
C. Research Blood Samples (collected at imaging visits) 
 Additional 2 tubes of blood will be stored for possible 
additional testing (not to include genetic or DNA 
analysis).  
 
3.2.1 Statin titration 
 
 
 
Statin medications will be titrated over the initial 6 months of the 
study to reach  protocol defined LDL cholesterol targets.  Should a 
participant’s LDL fluctuate after the 6 month visit, bringing them 
outside of their target range, statin dosage may be increased or 
decreased as necessary to return them to their protocol assigned 
target.  Participants who have not reached their LDL target after the 
6 month dose adjustment will be removed from study treatment as 
per off-treatment criterion 3, below. (3.4.1) 
 
 
3.2.2 Response to abnormal results 
 
All clinically abnormal test results will be relayed to 
participants’ primary care physician(s) or other designated 
third party.  Participants will be instructed to consult with 
their physician for follow up and referral to specialists as 
appropriate.   
In addition, abnormal laboratory values potentially due to 
statin treatment (ALT, AST, alkaline phosphatase, CK > 
1000 U/L) that are asymptomatic and less than 3 times the 
upper limit of normal as specified by the NIH Clinical Center 
clinical laboratory will be repeated within 2 weeks of the 
initial result.  If results are stable or improved, further testing 
will occur at normally scheduled study intervals.  Should 
results worsen, increases in statin dosage that immediately 
preceded the abnormal result will be reversed and laboratory 
results repeated in 2 weeks.  ALT, AST, alkaline 
phosphatase reaching more than 3 times the upper limit of 
normal or CK >1000 U/L will be considered a serious 
adverse event as per section 8.1  
 


 
 
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3.3 
Concurrent Therapies 
N/A 
3.4 
Criteria for removal from Treatment/Protocol 
3.4.1 Off Treatment Criteria: 
 
Subjects who come off treatment will be returned to usual 
care for cardiac risk factors as directed by their primary 
physician.  If they consent to continue imaging follow up, 
they will complete imaging as per protocol and be analyzed 
according to their original treatment group assignment.   
 
1. 
Occurrence of a clinical cardiovascular event including 
myocardial infarction, acute coronary syndrome, angina, 
heart failure, stroke or revascularization.  
 
2. 
Inability to continue on study medications (adverse reaction, 
not wanting to adhere to the study medications) 
  
3. 
Inability to reach our study LDL target after 6 months of 
titration (study visit 4) 
 
4. 
Elevations of liver enzymes three times the upper limits of 
normal or any elevation accompanied by symptoms 
compatible with hepatitis, i.e.: fatigue, sluggishness, 
anorexia and weight loss.  
 
5. 
Myopathy defined as muscle pain with serum creatinine 
kinase concentrations > 1000 U/L.  
3.4.2 Off Study Criteria 
 
Request of the patient or the attending physician.  
 
Any other clinical or laboratory abnormality which cannot be 
confidently excluded as a side effect from study medications 
will lead to discontinuation of an individual patient from the 
trial. 
 
Subjects who come off study for any reason will be referred back to 
their primary physician. 
 


 
 
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24 
4.0 
Supportive Care 
Study investigators and support staff will provide further 
consultation to participants by in-person visits, phone or electronic 
communication as needed to address participant concerns 
regarding study therapy or imaging evaluation.  
 
5.0 
Data Collection and Evaluation 
5.1 
Data Collection 
Standard forms for patient history, labs, imaging results. 
Vital status will be recorded on a case report form.  Complete 
records must be maintained on each patient, which will consist of 
the hospital chart with any supplementary information obtained 
from patient, outside laboratories, progress notes, reports, consults, 
or tests. 
 
The relational database storing the entire information set will be 
based on coded identification. The confidentiality and security of the 
data files in the computer will be maintained by ensuring password 
protection on all computer accounts. Protection against loss of data 
is essential to our data management. Quality control procedures will 
also include:  
1) Assurance or the prevention of possible errors;  
2) Assessment, or the detection of errors after they have occurred 
and;  
3) Feedback, or the correction of system failures which originated the 
error and is necessary to avoid errors in the future. Detailed 
checklists are used for data collection and trial procedures.  
 
Any protected patient information will be stored on a password 
protected secure database at NIH.  Any information will be de-
identified by study ID # and cleaned of PHI.  
5.2 
Response Criteria 
A.  Lipid targets will be used as response criteria study. 
5.3 
Toxicity Criteria 
Table: Safety Parameters to be monitored during the study 
Safety 
issues 
Measure 
Method 
Concern Discontinuation Discont. 
Freq. 
Liver 
Function 
ALT, AST 
Standard 
2 x 
normal 
3 x normal 
2% 


 
 
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25 
 
6.0 
Statistical Section 
 
 
Data from the recently concluded NIA Plaque Study, a randomized 
double-blind trial of the effect of niacin vs. placebo on MRI plaque volumes 
were collected on 145 subjects at baseline, and at 18-month follow-up. For 
the primary endpoint in the proposed study, carotid wall volume, the 
standard deviation of the differences between 18 months and baseline 
was 125 mm3, combining data from both the left and right arteries. The 
baseline mean for the entire group was 300.0. Since the proposed study 
has a longer duration (24 months) than the NIA Plaque Study, and since 
we have the benefit of improvements in MRI technology, we anticipate a 
larger effect size than was seen in the NIA Plaque Study. The sample size 
calculations were based on finding a 40% decrease in plaque volume in 
the image-guided arm compared to a 20% decrease in the conventional 
treatment arm at 24 months using a two-sample t-test.  The table below 
shows the power to detect this difference at the 5% level of significance, 
assuming 80 subjects in each group. These power calculations were 
based on comparing the change from baseline at a single time point. 
However, the primary analysis will employ a mixed model, which will 
include multiple observations per patient. Therefore, 80 patients in each 
group will certainly provide adequate power. As discussed below we 
assume that the attrition rate will be 0.20 at the 24-month follow-up. Thus, 
recruiting 200 study participants will be sufficient for this study. These 
calculations were based on the optimal allocation of equal numbers to the 
two arms. However a 3/1 ratio of image-guided to conventional therapy did 
not meaningfully reduce the power.   
 
 
 
 
 
Power of a two-sample t test to detect the indicated difference in change from 
baseline at 24 months 
 
For the secondary end-point of this study, the task is to test the null 
hypothesis that the hazard rate, which is assumed to be constant across 
all study months, is identical in the two groups (image guided vs. 
Liver 
Function 
Alk. 
Phosphatase 
Standard 
2 x 
normal 
3 x normal 
<1% 
Muscle 
Injury 
CK 
Standard 
3 x 
normal 
>1000 U/L 
<1% 
Hepatitis Symptoms/LFTs 
History 
LFT 
elev. 
Clin. Diagn. 
<1% 
 
Decrease in 
plaque volume  
(Image guided 
arm) 
Decrease in Plaque Volume (Control Arm) 
 
15% 
20% 
25% 
35% 
0.85 
0.62 
0.33 
40% 
0.96 
0.85 
0.62 
45% 
0.99 
0.96 
0.85 


 
 
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traditional risk-factor based care). This hypothesis will be tested in a study 
in which subjects are entered and then followed until either (a) the terminal 
event occurs, or (b) they drop out of the study, or (c) the study ends and 
the patient is censored while still being actively followed. The study design 
calls for an accrual period of 50 months and a follow-up period of 24 
months. Computation of power for this analysis is based on a hazard ratio 
of 0.50.  Specifically, it assumes hazard rates of 1.00 for the standard care 
group, versus 0.50 for the image guided group. Since the hazard rate is 
constant across months, this is equivalent to median survival times of 0.69 
years for the standard treatment versus 1.39 years for the image guided 
intervention group.  
 
The power analysis for the secondary outcome (clinical events) was based 
on the paper by Brown et al.24 This paper reported mortality rates at 30 
months in two treatment groups (2/48 = 0.042 and 3/46 = 0.065) and a 
control (10/52 = 0.192). We used these rates, as well as the combination 
for the two treatment groups (5/94 = 0.053). The calculation of power was 
based on the log-rank test(25) assuming a 24 month study. Using a two-
sided test at the 5% level of significance, we obtained the following 
results. 
 
Power of the log-rank to detect the indicated difference from control 
     Treatment 
Mortality Rate 
Sample 
Size/group 
0.042 
0.053 
0.065 
50 
0.57 
0.47 
0.38 
80 
0.82 
0.71 
0.59 
100 
0.91 
0.82 
0.70 
 
We assume that the attrition rate will be 0.20 in the 24-month follow-up. 
Thus, recruiting 200 study participants with 160 anticipated to complete 24 
months of follow-up will be sufficient for this study. 
 
 
 
Data Analysis: 
 
1. The intent-to-treat and missing data: 
 
The intent-to-treat (ITT) approach will be used for the primary analysis. 
According to this generally recommended approach, comparisons are 
made according to randomized treatment assignment, regardless of any 
changes in dose, schedule or treatment arm. In an ITT analysis, all 
randomized study participants are included in their assigned treatment 
groups, regardless of compliance with the assigned treatment regimen. 
On the other hand, the weakness of ITT is that it assesses the effect of 
treatment for subjects known not to have used the treatment enough to 
have any effect. While conventional ITT will be the method used to 
analyze and report the primary results, in order to derive valid estimates of 


 
 
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treatment effect accounting for compliance with therapy, model-based 
analytical methods will also be employed, and non-ITT analysis will be 
performed.   
 
In fact, in the present study, we do not foresee noncompliance as a 
problem since treatment administration is under the control of the study 
physician rather than the patient.  Dropout, however, is always a potential 
problem. In this study we have assumed a dropout rate of 20%, since we 
anticipate a lower dropout rate than the 25% in the previous trial.  This is 
because we are using three scans over two years rather than four over 18 
months as in the previous study, and many of the previous dropouts were 
related to MRI anxiety. Thus we do not anticipate problems with 
differential dropout.  In addition, approximately one-third of the dropouts in 
the previous study were due to problems with niacin flushing, which again 
will not be a problem in the present study. 
 
2. Multiple outcome measures: 
 
In this clinical trial, we will evaluate multiple outcome measures: changes 
in plaque architecture and composition measured by MRI, and time to 
events, including the incidence of cardiovascular and cerebrovascular 
outcomes and disease-specific death. The following approaches to 
evaluate multiple outcome measures will be implemented: (i) defining a 
primary outcome measure; (ii) correcting for multiple testing, such as 
Bonferroni adjustment; (iii) with data on major clinical events, adopting a 
combined endpoint, such as time to first cardiovascular event or death, 
whichever occurs first.  
 
3. Data Analysis: 
  
Standard statistical methods(24) will be used to describe the demographic 
characteristics, clinical manifestations and basic summary statistics as 
rates or means (medians). Confidence intervals will also be computed. If 
necessary, permutation methods (26) will be employed.   
 
For Hypotheses 1, 2, and 4:  
 
Linear mixed (random-effects) models(27) will be used to study differential 
changes over time in plaque size and composition and drug dosage 
between the two treatments. Each model will include main effects of time 
from baseline and treatment, with interactions tested separately. To 
decide on the correlation structure for these models, variation due to 
random effects, serial correlation and measurement error will be examined 
using the variogram. These models will also be used to isolate specific 
comparisons of outcome variables at specific time points between the two 
arms.  The required assumptions of normally distributed errors and 
random effects can be checked by an analysis of standardized residuals, 
which are now available for the mixed model. In the event that the 
assumptions are not satisfied, usually because of skewed error 
distributions, data transformations from the Box-Cox power family will be 
considered.  The most commonly used member of this family is the 
logarithmic transformation, which usually corrects a problem with right 
skewness.  
 


 
 
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For Hypothesis 3:  
 
For the time-to-event data, both the Kaplan-Meier estimate and the Cox 
proportional hazards model will be employed.  The primary analysis will 
compare the two treatments using a log-rank test.  Secondary analyses 
will use the Cox model to include adjustment for covariates.  A non-
parametric proportional hazards model will also be used to explore 
possible transformations of independent variables in the models(28). 
 
For Hypothesis 5, 6, and 7: 
 
Using appropriate parametric and non-parametric tests at and between 
both the baseline and 6 month time points, a comparison of the presence 
or absence of atherosclerotic plaque by PET and CT / MRI will be 
performed.  FDG accumulation (with both TBR and SUVmax) will be 
compared across different plaque morphology and compositions defined 
by MR / CT (for example, presence of a lipid core or calcification).  
Correlation between imaging findings and changes will be made with age, 
gender, traditional risk factors (height, weight, hypertension, etc.), 
absolute values and changes in statin dose, total cholesterol, LDL, HDL, 
triglycerides and hematological biomarkers markers of inflammation, 
thrombosis and atheroprotection. 
 
For Hypothesis 8: 
Agreement between the two blinded readers of semiquantitative measures 
of CT angiographic stenosis will be measured using weighted kappa.  
Quantitative analyses of coronary arterial wall volume, lumen volume and 
plaque composition will be assessed using the intraclass correlation 
coefficient (ICC) and Bland-Altman plots.   
   
7.0 Human Subject Protection  
7.1 Rationale for Subject Selection  
Individuals over age 55 from all racial/ethnical groups are eligible to 
participate.  NIH employees over age 55 who meet the eligibility 
requirements are eligible to be screened and considered for protocol 
participation.  
 
Recruitment and enrollment of NIH employee subjects will be 
consistent with NIH HRPP SOP 14 F Section 3.1.  We intend to allow 
enrollment of staff who are affiliated or subordinate to the Principal 
Investigator, including technologists, nurses, scientists, students and 
family members.  We believe we can offer them the opportunity to 
participate without coercion.  Consent for such subjects will not be 
obtained from individuals in their supervisory chain of command.  Refer 


 
 
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29 
to the NIH Policy Manual, 2300-630-3 - Leave policy for NIH 
Employees Participating in NIH Medical Research Studies. 
 
This age group is the most likely group to suffer the clinical events 
consequent to atherosclerosis. Atherosclerosis and concomitant 
cardiovascular events are the leading cause of death in all major 
racial/ethnic subgroups in industrialized nations, Efforts to reduce the 
burden of cardiovascular disease is powerfully relevant to persons of 
all ethnicities.  Our planned enrollment has been selected to be 
representative of the general gender and ethnic demographic 
subgroups of the greater Washington DC area (appendix F).  The 
advent of MRI techniques powerful enough to allow for precise 
quantification of plaque growth and regression, as well as alterations of 
plaque architecture and composition, has made available a number of 
novel indices of atherosclerotic burden and plaque vulnerability. This 
study is designed to investigate the comparative effectiveness of 
image guided lipid therapy with standard NCEP guided therapy with 
HMG-CoA reductase agents on the progression of carotid and 
coronary atherosclerosis as sub-clinical markers of cardiovascular 
atherosclerotic disease. 
 
PET Substudy 
 
A subgroup of 60 patients will be recruited to participate in PET 
scanning  
 
Reproducibility Substudy 
A subgroup of 60 participants who had one RR interval CT scan will be 
asked to return 4 weeks after their initial scan for a second scan using 
the same protocol.  The inclusion criteria for this substudy -- single 
heartbeat (one RR interval) scan with <10.5 mSv  estimated dosage --
are selected to keep radiation exposure as low as can be achieved 
while assessing the reproducibility limits of this method.  Additionally, 
the protocol indicated and reproducibility scans will cumulatively 
administer less than the 21 mSv radiation dosage specified in the 
consent document.  Patients will not undergo calcium scanning during 
the reproducibility scan and they will not be eligible for the PET 
substudy.   Sixteen to twenty-four patients will be selected from three 
groups: (a) patients with a calcium score of  0-99, (b) patients with a 
calcium score -100-399 and (c) patients with a calcium score of > 400.  
These 60 scans will be interpreted by two readers, allowing 
assessment of both intra and interobserver variability as well as 
repeatability limits.     
 
A comprehensive strategy of advertising and recruitment through the 
NIH clinical center patient recruitment and referral center will be 


 
 
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30 
utilized including radio and internet PSAs as well as print flyers. 
(Appendix G) The Johns Hopkins Clinical Trial Unit database will also 
be used to identify qualifying participants, pending IRB approval at that 
institution.  This database contains a rich population of patients in 
preventive cardiology clinics who have identified themselves as 
interested in participation in clinical trials. 
 
Searches of the electronic medical record, radiology records and 
patient registries at Suburban hospital will be performed to identify and 
recruit patients meeting inclusion criteria for this study under a HIPAA 
waiver granted by the Suburban Privacy Board. 
7.2 Participation of Children: 
Atherosclerotic disease is not a disease of childhood and will not be 
eligible for participation in this study, based on the fact they are 
unlikely to have this disease. 
 
 
7.3 Evaluation of Benefits and Risks/Discomforts:  
 
Phlebotomy  
 
Associated risks include anemia and hematoma and minor pain at the 
puncture site.   
 
Beta-Blockers (Atenolol and Metoprolol 
 
Atenolol and metoprolol are FDA approved selective β1 receptor 
blocker used in treatment of several diseases of the cardiovascular 
system, especially hypertension, angina or myocardial infarction. The 
side-effects include tiredness and dizziness (10%), depression  (5%), 
rash (5%), diarrhea (5%) shortness of breath (3%), chest pain (1%), 
wheezing (1%). Palpitations, congestive heart failure, peripheral 
edema, syncope, chest pain, dry mouth, gastric pain, constipation, 
flatulence, digestive tract disorders, heartburn, hypotension, mental 
confusion, short-term memory loss, headache, somnolence, 
nightmares, and insomnia reported in very rare instances (<1%). 
 
Calcium-channel Blockers (Diltiazem) 
 
Diltiazem is a FDA approved cardiovascular medication for the 
treatment of hypertension, angina or rate control of atrial 
fibrillation/flutter or conversion of supraventricular tachycardia.  The 
side-effects of chronic use include lower extremity edema (2-15%), 
headache (5-12%), first degree AV block (2-8%), bradycardia (2-6%), 


 
 
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hypotension (<2%-4%), vasodilation (2-3%), extrasystoles (2%), 
flushing (1-2%), dizziness (3-10%), nervousness (2%), rash (1-4%), 
dyspepsia (1-6%), constipation (<2-4%), vomiting (2%), diarrhea (1-
2%), weakness (1-4%), myalgia (2%), rhinitis (<2-10%), pharyngitis (2-
6%), dyspnea (1-6%), bronchitis (1-4%), cough (<3%) and sinus 
congestion (1-2%). 
 
StatinTherapy 
 
HMG CoA-Reductase inhibitors (statins) are generally well tolerated.    
Clinically important adverse effects of the drugs include increases in 
serum transaminase concentrations and myositis, with and without 
complicating rhabdomyolysis. (29)  Statin monotherapy can result in 
elevation of liver enzymes, most often ≤3 times the upper limit of 
normal.  These elevations typically normalize without lasting injury 
upon discontinuation of the drug.  Their clinical significance is 
uncertain given the extremely rare occurrence of statin related toxic 
hepatits(16).  
 
In 7 studies to date reporting rates of clinical myositis, elevation of 
creatinine kinase (CK) > 10 times the upper limit of normal and 
rhabdomyolysis, the combined incidence of these events has been 
less than 0.7%(10, 31-35).The highest reported rate of rhabdomyolysis 
was 0.53%, observed with simvastatin 80 mg daily. (36) 
 
The use of high dose, intensive statin therapies to achieve very low 
LDL levels is a recent development. Available data, including three 
large randomized controlled trials (the A to Z,  TNT and IDEAL 
studies), indicate that high-dose statins (atorvastatin 80 mg daily, 
simvastatin 80 mg daily) are associated with low rates of serious 
musculoskeletal (<0.6%) and hepatic (<1.3%) injury.  (33, 34, 36, 37) 
 
Ionizing Radiation 
 
Low dose CTA angiography and FDG PET/CT (as used in this 
protocol) carries a conservatively estimated lifetime additional risk of 
malignancy less than 0.2% in women and less than 0.1% in men, on a 
background lifetime risk of approximately 30%.38-40The primary 
prevention population targeted for this study is unlikely to receive 
significant degrees of medical radiation during the 24 months of study 
follow up. 
 
This study uses statin drugs for the FDA approved indications of 
treatment of hypercholesterolemia.  The study is not designed or 
intended to test new indications, dosages, routes or study populations 
for statin drugs.  The research question underlying this protocol is 
strictly limited to the issue of risk stratification approaches, not to how 
that risk is treated.  The use of statins in this study meets the six 
conditions for IND exemption. 


 
 
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1. it is not intended to be reported to FDA in support of a new 
indication for use or to support any other significant change in the 
labeling for the drug; 
2. it is not intended to support a significant change in the advertising 
for the product; 
3. it does not involve a route of administration or dosage level, use in a 
subject population, or other factor that significantly increases the risks 
(or decreases the acceptability of the risks) associated with the use of 
the drug product; 
4. it is conducted in compliance with the requirements for IRB review 
and informed consent [21 CFR parts 56 and 50, respectively]; 
5. it is conducted in compliance with the requirements concerning the 
promotion and sale of drugs [21CFR 312.7]; and 
6. it does not intend to invoke provisions regarding emergency 
research under 21 CFR 50.24. 
 
Gadolinium enhanced MR 
 
The use of MR contrast containing gadolinium chelates is generally 
considered to be safe, with an extremely rare incidence of idiopathic 
allergic reactions.  Use in a population with severe (stage 4 to 5) renal 
dysfunction is the exception to this rule.  Patients with severe or end-
stage renal impairment and concomitant gadolinium chelate exposure 
are at risk for development of the fibrosing disorder nephrogenic 
fibrosing dermopathy (NSF), with 2.5-5% of patients with end-stage 
renal disease on dialysis developing NSF subsequent to gadodiamide 
exposure.  The FDA currently defines the at-risk population as patients 
with estimated GFR <30 mL/min/m2 or those with any degree of renal 
dysfunction due to the hepatorenal syndrome or peri-hepatic transplant 
period.41, 42 The FDA has no reports of NSF in patients with mild-to-
moderate renal insufficiency (ie, eGFR>29 ml/min/m2) or normal renal 
function 
(http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/200
7/ucm108919.htm).  To ensure participant safety and provide a wide 
safety margin, participants with estimated GFR < 45 mL/min/m2 will be 
ineligible for gadolinium chelate contrast administration during this 
study.43 
 
Iodinated contrast  
 
The primary known risks of nonionic iodinated contrast as utilized in 
MDCT angiography are hypersensitivity reactions and contrast induced 
nephropathy. Mild to moderate adverse events such as nausea, 
injection site pain or urticaria occur in less than 3 percent of patients.  
Serious adverse events, such as hypotensive collapse, shock and 
death are reported in less than 1 in 10,000 patients.  These reactions 
are generally considered idiosyncratic. Contrast induced nephropathy 
(CIN) is defined by an increase in creatinine more than 1 mg/dL or 
50% above baseline.  The risk of CIN in patients with normal renal 
function is considered to be negligible. The inclusion criteria for this 


 
 
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study require baseline GFR >45 mL/min/m2 as calculated by the 
MDRD equation to minimize risk of nephropathy. Furthermore, 
injection of less than 100 ccs of iodinated contrast medium is 
considered to present minimal risk of CIN.  The proposed MDCT 
angiographic protocol utilizes ~60cc of contrast.44   
 
F-18 Fluorodeoxyglucose 
 
F-18 fluorodeoxyglucose (FDG) is an analog of glucose with an 
excellent safety record. In a four year multicenter study of 81,801 FDG 
administrations, involving one-third of the United States PET facilities, 
not a single adverse reaction was detected with 95% confidence limits 
from 0-3.7/100,000.44 This finding is consistent with observations made 
across all radiopharmaceuticals. In a prospective study of over 
750,000 administrations in 18 major United States medical centers the 
prevalence of reactions was 2.3/100,000 with 95% confidence limits of 
1.2-3.4/100,000.46 
7.4 Risks/Benefits Analysis 
The principal risks to participants are intensive statin therapy, exposure 
to ionizing radiation as part of the coronary CT angiogram, receipt of 
iodinated contrast and receipt of gadolinium based contrast.  As noted 
in 7.3, above, large clinical trials have demonstrated low rates of 
significant adverse events due to statins, few if any of which persist 
after drug discontinuation.  The study population has been specifically 
selected to be at the lowest risk for ionizing radiation, and the CT 
protocol carefully tailored to ensure delivery of the lowest possible 
dosage necessary to generate diagnostic images.  The limitation of 
enrollment to patients with GFR > renders the risk of iodinated and 
gadolinium based contrast negligible. 
 
The level of risk to the research participants was initially determined to 
be greater than minimal risk (45 CFR 46 102). As of January 2017, the 
study status of this protocol changed to “data analysis only” and the 
level of risk of this study is now minimal.  
 
This research involves the prospect of direct benefit to individual 
subjects through potential identification of clinically silent 
atherosclerotic disease and according intensification of statin therapy 
that would not otherwise be indicated in usual clinical care.  This 
carries the likelihood of significant reduction (16-21% relative risk 
reduction) of the risk of clinical cardiovascular events.47  
7.5 Consent Process and Documentation 
 
Patients asked to participate in PET imaging will be consented separately for 
their participation in the main protocol and the substudy. Patients asked to 
participate in the Reproducibility Substudy will be consented separately for their 
participation in the main protocol and the substudy.  The investigational nature 


 
 
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34 
and objective of this trial, the procedures involved and their possible risk and 
discomforts, potential benefits, and possible alternative therapies will be 
explained to participants.  The subject will be provided with a copy of the consent 
with enough time to review it and ask questions prior to the consent process.  
Participants will be enrolled after eligibility criteria have been determined and a 
signed informed consent document has been obtained.  Consent for NIH 
employee will not be obtained from individuals in their supervisory chain of 
command. 
 
The following investigators are authorized to obtain informed consent 
from the study subjects and are marked with an asterisk (*) on page 1 
of the protocol:  
- .  
-  
- . 
- Mark Ahlman, M.D. 
- 
 
7.6 Data Safety and Monitoring 
The entire study data set will be managed by the principal investigator.  
The entire data set will be contained in a secure database located on 
the NIH server.  The forms to record data for this study will be 
generated and carefully reviewed for completeness, discrepant, 
inappropriate, and illogical responses. The data will checked for 
duplicate entries, with range checks on each field and consistency 
checks between fields with linked information.  In cases of incoherent 
or missing data, the study coordinator will be immediately contacted 
and, if necessary, the form returned for CRF correction by the data 
manager. If multiple problems are found, a larger percentage of patient 
records will be audited. Non-image study data will be managed through 
the NICHD Clinical Trials Database system and stored on secure, 
redundant servers.  Study image data will reside on the PACS.  
A data safety and monitoring board will review all laboratory and safety 
data.  At regular 6-month intervals the DSMB will monitor the safety 
and efficacy of image guided therapy compared with the standard 
therapy control arm. This will include evaluation of enrollment, 
compliance, follow-up, laboratory results, data management, and 
quality control. The DSMB will decide at each of these reviews whether 
the study will continue as originally designed. Efficacy analyses will be 
conducted for two interim analyses (at the end of year one and year 
two) and one final evaluation. The members of the DSMB, pending 
acceptance, will be Kiang Liu, PhD (Northwestern University, Chicago) 
– biostatistics and epidemiology; Victor Ferrari, MD (University of 
Pennsylvania) – cardiology and cardiovascular imaging, and Gary 
Plotnick, MD (University of Maryland)—general cardiology.   


 
 
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Data confidentiality:   
 
Patient image data will be maintained on PACS database systems 
within the Department of Radiology with security and redundancy at 
the level of the clinical PACS system used by the NIH clinical center 
The confidentiality and security of the data files containing PHI will be 
maintained by ensuring password protection on all computer accounts. 
Protection against loss of data is essential to our data management. 
Copies of the study database files will reside in an independent back-
up hard drive.   
Data reporting will be done through presenting in national meetings 
and publishing in journals.   
   
7.7 Compensation 
Patients will not receive direct financial compensation for participation in 
the main study.  They will receive statin medication without charge for 
statins available on formulary at the NIH clinical center (simvastatin, 
atorvastatin).  Patients who are already taking non formulary statins 
(lovastatin, fluvastatin, pravastatin and do not wish to switch to a 
formulary agent will not be compensated for their drug therapy.   
Participants will be compensated for travel to and from the NIH Clinical 
Center.  For NIH Employees enrolled on this study, refer to NIH Policy 
Manual, 2300-630-3 – Leave policy for NIH Employees Participating in 
NIH Medical Research Studies.  
 
Reimbursement for the PET and CT reproducibility substudies will be 
consistent with NIH guidelines.   
 
For the PET substudy, participants will receive up to $450 total for the 3 
additional visits based on the following: 
 
 Phlebotomy: 1 inconvenience unit 
 IV placement: 1 inconvenience unit 
 PET with IV contrast: 8 inconvenience units 
 MRI with IV contrast: 8 inconvenience units  
 Maximum $50 for visit ($20 for the first hour and $10 for each 
following hour with a maximum of 4 hours per visit) 
For the CT Reproducibility substudy, participants will receive up to $150 
for the visit based on the following: 
 
 Phlebotomy: 1 inconvenience unit 


 
 
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36 
 IV placement: 1 inconvenience unit 
 CT with IV contrast: 10 inconvenience units 
 Maximum $30 for visit ($20 for the first hour and $10 for each 
following hour with a maximum of 2 hours per visit) 
 
7.8 Conflicts of Interest 
This study has no external sponsors or funding sources.  No 
investigator has a relevant conflict of interest.  
8.0 
Safety Reporting Requirements:  
8.1 Adverse Event Definition  
 
Expected Events not reportable 
Bruising or extravasation from the intravenous injection, mild 
contrast allergies that do not require treatment (e.g. headache, 
pain at site, warmth, flushing, nausea, less than 5 hives) and 
additional findings on the MRI that require additional workup 
outside of the study. 
 
Asymptomatic bradycardia (HR <60 bpm) or hypotension 
(systolic blood pressure <90 mmHg) following beta blockade or 
nitrates. 
 
Orthostatic symptoms (excluding syncope) following beta 
blockade or nitrates that resolve without medical intervention.  
 
Muscle discomfort or myalgias without significant (>3 x ULN) 
elevations of CK. 
 
Expected Events reportable at time of Continuing Review 
 
ALT, AST or alkaline phosphatase elevations between 2-3 
times the upper limit of normal or requiring discontinuation of 
statin therapy.  (Elevations >3 times the upper limit of normal 
will be considered a serious adverse event as per below).   
 
Serious Adverse Event reporting 
 A Serious adverse event is defined as one of the following (in 
accordance with FDA 21 CFR312.32 and the NIH intramural 
guidance for principal investigators on reporting adverse events) 
 death from any cause, 


 
 
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 life threatening event, i.e., an event that places the 
subject, in the view of the investigator, at immediate risk 
of death from the event as it occurred. 
 any event that requires or prolongs in-patient 
hospitalization 
 any event that results in persistent or significant 
disability/incapacity  
 any congenital anomaly/birth defect diagnosed in a  
child of a subject who participated in this study. 
 other medically important events that in the opinion of 
the investigator may jeopardize the subject or may 
require intervention to prevent ongoing injury.   
 
 
Unexpected Adverse Events 
 
Unexpected adverse events are those that are not described in the 
published medical literature, in this protocol, or in the informed consent, 
as being associated with statin therapy and routine CT or MR scanning.  
Such events might include concurrent unrelated medical illnesses such 
as ischemic heart disease, stroke, cancer, pneumonia, and other 
common illnesses seen in the general population but we will attempt to 
screen for these illnesses with the history and physical exam. 
 
These unexpected adverse events will be recorded by the PI, but if they 
are clearly unrelated to the protocol they will not be reported to the IRB.  
If they are coincident with research procedures and are possibly related 
to the protocol they will be reported to the IRB according to NIH 
guidelines. 
 
8.2 
IRB Adverse Event Reporting Guidelines 
All serious events will be recorded in the patient chart and in the research 
folder maintained by the research nurse.  In accordance with NHLBI 
policy, serious adverse events that do not meet criteria for unanticipated 
problem will be reported to clinical director and IRB chair within 14 days 
of learning of event using the SAE form in PTMS.  Deaths must be 
reported within 7 days. 
 
All non serious adverse events will be tracked and reported to the IRB 
with the annual continuing review report.   
  
8.3 IND/IDE: 
    An investigational device exemption is not applicable for this study. 
 


 
 
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The magnetic resonance magnets and coils used to perform carotid 
imaging are 510k approved devices being used in accordance with their 
labeling (21 CFR 812 § 812.2.(c)).  Imaging sequences that are not 
commercially available (research sequences or works-in-progress) may 
be used during image acquisition.  These sequences conform to 
marketed device standards with respect to FDA established safety criteria 
for static field strength, acoustic noise, dB/dt, RF heating, biocompatibility 
and performance.  Consistent with an IDE exempt investigation, any non-
commercial imaging sequences will be used solely to address the 
research questions of this protocol, and not to address the safety or 
effectiveness of the sequences themselves.   
 
  The CT scanners used to perform CT angiography are 510k approved 
devices being used in accordance with their labeling (21 CFR 812 § 
812.2.(c)). No investigational CT applications are proposed.  
9.0 
Multi-Institutional Guidelines: N/A 
10.0 
Pharmaceutical Information  
Beta Blocker (Package insert) Clinical Pharmacology information: 
Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in 
vivo animal studies have shown that it has a preferential effect on 
beta1 adrenoreceptors, chiefly located in cardiac muscle. This 
preferential effect is not absolute, however, and at higher doses, 
Lopressor also inhibits beta2 adrenoreceptors, chiefly located in the 
bronchial and vascular musculature. 
 
Clinical pharmacology studies have confirmed the beta-blocking 
activity of metoprolol in man, as shown by (1) reduction in heart rate 
and cardiac output at rest and upon exercise, (2) reduction of systolic 
blood pressure upon exercise, (3) inhibition of isoproterenol-induced 
tachycardia, and (4) reduction of reflex orthostatic tachycardia. 
  
Relative beta1 selectivity has been confirmed by the following: (1) In 
normal subjects, Lopressor is unable to reverse the beta2 -mediated 
vasodilating effects of epinephrine. This contrasts with the effect of 
nonselective (beta1 plus beta2) beta blockers, which completely 
reverse the vasodilating effects of epinephrine. (2) In asthmatic 
patients, Lopressor reduces FEV1 and FVC significantly less than a 
nonselective beta blocker, propranolol, at equivalent beta1-receptor 
blocking doses. 
  
Lopressor has no intrinsic sympathomimetic activity, and membrane-
stabilizing activity is detectable only at doses much greater than 
required for beta blockade. Lopressor crosses the blood-brain barrier 


 
 
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and has been reported in the CSF in a concentration 78% of the 
simultaneous plasma concentration. Animal and human experiments 
indicate that Lopressor slows the sinus rate and decreases AV nodal 
conduction. 
 
In controlled clinical studies, Lopressor has been shown to be an 
effective antihypertensive agent when used alone or as concomitant 
therapy with thiazide-type diuretics, at dosages of 100-450 mg daily. In 
controlled, comparative, clinical studies, Lopressor has been shown to 
be as effective an antihypertensive agent as propranolol, methyldopa, 
and thiazide-type diuretics, and to be equally effective in supine and 
standing positions.  
 
The mechanism of the antihypertensive effects of beta-blocking agents 
has not been elucidated. However, several possible mechanisms have 
been proposed: (1) competitive antagonism of catecholamines at 
peripheral (especially cardiac) adrenergic neuron sites, leading to 
decreased cardiac output; (2) a central effect leading to reduced 
sympathetic outflow to the periphery; and (3) suppression of renin 
activity. 
 
By blocking catecholamine-induced increases in heart rate, in velocity 
and extent of myocardial contraction, and in blood pressure, Lopressor 
reduces the oxygen requirements of the heart at any given level of 
effort, thus making it useful in the long-term management of angina 
pectoris. However, in patients with heart failure, beta-adrenergic 
blockade may increase oxygen requirements by increasing left 
ventricular fiber length and end-diastolic pressure. 
 
Although beta-adrenergic receptor blockade is useful in the treatment 
of angina and hypertension, there are situations in which sympathetic 
stimulation is vital. In patients with severely damaged hearts, adequate 
ventricular function may depend on sympathetic drive. In the presence 
of AV block, beta blockade may prevent the necessary facilitating 
effect of sympathetic activity on conduction. Beta2-adrenergic 
blockade results in passive bronchial constriction by interfering with 
endogenous adrenergic bronchodilator activity in patients subject to 
bronchospasm and may also interfere with exogenous bronchodilators 
in such patients. 
 
In controlled clinical trials, Lopressor, administered two or four times 
daily, has been shown to be an effective antianginal agent, reducing 
the number of angina attacks and increasing exercise tolerance. The 
dosage used in these studies ranged from 100-400 mg daily. A 
controlled, comparative, clinical trial showed that Lopressor was 
indistinguishable from propranolol in the treatment of angina pectoris. 


 
 
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In a large (1,395 patients randomized), double-blind, placebo-
controlled clinical study, Lopressor was shown to reduce 3-month 
mortality by 36% in patients with suspected or definite myocardial 
infarction.  
 
Patients were randomized and treated as soon as possible after their 
arrival in the hospital, once their clinical condition had stabilized and 
their hemodynamic status had been carefully evaluated. Subjects were 
ineligible if they had hypotension, bradycardia, peripheral signs of 
shock, and/or more than minimal basal rales as signs of congestive 
heart failure. Initial treatment consisted of intravenous followed by oral 
administration of Lopressor or placebo, given in a coronary care or 
comparable unit. Oral maintenance therapy with Lopressor or placebo 
was then continued for 3 months. After this double-blind period, all 
patients were given Lopressor and followed up to 1 year. 
 
The median delay from the onset of symptoms to the initiation of 
therapy was 8 hours in both the Lopressor- and placebo-treatment 
groups. Among patients treated with Lopressor, there were 
comparable reductions in 3-month mortality for those treated early (≤8 
hours) and those in whom treatment was started later. Significant 
reductions in the incidence of ventricular fibrillation and in chest pain 
following initial intravenous therapy were also observed with Lopressor 
and were independent of the interval between onset of symptoms and 
initiation of therapy.  
 
The precise mechanism of action of Lopressor in patients with 
suspected or definite myocardial infarction is not known. 
 
In this study, patients treated with metoprolol received the drug both 
very early (intra-venously) and during a subsequent 3-month period, 
while placebo patients received no beta-blocker treatment for this 
period. The study thus was able to show a benefit from the overall 
metoprolol regimen but cannot separate the benefit of very early 
intravenous treatment from the benefit of later beta-blocker therapy. 
Nonetheless, because the overall regimen showed a clear beneficial 
effect on survival without evidence of an early adverse effect on 
survival, one acceptable dosage regimen is the precise regimen used 
in the trial. Because the specific benefit of very early treatment remains 
to be defined however, it is also reasonable to administer the drug 
orally to patients at a later time as is recommended for certain other 
beta blockers. 
Iodine contrast (Package Insert) isovue (iopamidol)  injection, solution   


 
 
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Intravascular injection of a radiopaque diagnostic agent opacifies those 
vessels in the path of flow of the contrast medium, permitting 
radiographic visualization of the internal structures of the human body 
until significant hemodilution occurs. 
 
Following intravascular injection, radiopaque diagnostic agents are 
immediately diluted in the circulating plasma. Calculations of apparent 
volume of distribution at steady-state indicate that iopamidol is 
distributed between the circulating blood volume and other 
extracellular fluid; there appears to be no significant deposition of 
iopamidol in tissues. Uniform distribution of iopamidol in extracellular 
fluid is reflected by its demonstrated utility in contrast enhancement of 
computed tomographic imaging of the head and body following 
intravenous administration. 
 
The pharmacokinetics of intravenously administered iopamidol in 
normal subjects conform to an open two-compartment model with first 
order elimination (a rapid alpha phase for drug distribution and a slow 
beta phase for drug elimination). The elimination serum or plasma half-
life is approximately two hours; the half-life is not dose dependent. No 
significant metabolism, deiodination, or biotransformation occurs. 
 
Iopamidol is excreted mainly through the kidneys following 
intravascular administration. In patients with impaired renal function, 
the elimination half-life is prolonged dependent upon the degree of 
impairment. In the absence of renal dysfunction, the cumulative urinary 
excretion for Iopamidol, expressed as a percentage of administered 
intravenous dose is approximately 35 to 40 percent at 60 minutes, 80 
to 90 percent at 8 hours, and 90 percent or more in the 72-to 96-hour 
period after administration. In normal subjects, approximately one 
percent or less of the administered dose appears in cumulative 72- to 
96-hour fecal specimens. 
 
ISOVUE may be visualized in the renal parenchyma within 30-60 
seconds following rapid intravenous administration. Opacification of the 
calyces and pelves in patients with normal renal function becomes 
apparent within 1 to 3 minutes, with optimum contrast occurring 
between 5 and 15 minutes. In patients with renal impairment, contrast 
visualization may be delayed. 
 
Iopamidol displays little tendency to bind to serum or plasma proteins. 
 
No evidence of in vivo complement activation has been found in 
normal subjects. 
*Animal studies indicate that iopamidol does not cross the blood-brain 
barrier to any significant extent following intravascular administration. 


 
 
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42 
*ISOVUE (lopamidol Injection) enhances computed tomographic brain 
imaging through augmentation of radiographic efficiency. The degree 
of enhancement of visualization of tissue density is directly related to 
the iodine content in an administered dose; peak iodine blood levels 
occur immediately following rapid injection of the dose. These levels 
fall rapidly within five to ten minutes. This can be accounted for by the 
dilution in the vascular and extracellular fluid compartments which 
causes an initial sharp fall in plasma concentration. Equilibration with 
the extracellular compartments is reached in about ten minutes, 
thereafter the fall becomes exponential. Maximum contrast 
enhancement frequently occurs after peak blood iodine levels are 
reached. The delay in maximum contrast enhancement can range from 
five to forty minutes depending on the peak iodine levels achieved and 
the cell type of the lesion. This lag suggests that radiographic contrast 
enhancement is at least in part dependent on the accumulation of 
iodine within the lesion and outside the blood pool, although the 
mechanism by which this occurs is not clear. The radiographic 
enhancement of nontumoral lesions, such as arteriovenous 
malformations and aneurysms, is probably dependent on the iodine 
content of the circulating blood pool. 
 
In CECT head imaging, ISOVUE (lopamidol Injection) does not 
accumulate in normal brain tissue due to the presence of the blood-
brain barrier. The increase in x-ray absorption in normal brain is due to 
the presence of contrast agent within the blood pool. A break in the 
blood-brain barrier such as occurs in malignant tumors of the brain 
allows the accumulation of the contrast medium within the interstitial 
tissue of the tumor. Adjacent normal brain tissue does not contain the 
contrast medium. 
 
In nonneural tissues (during computed tomography of the body), 
iopamidol diffuses rapidly from the vascular into the extravascular 
space. Increase in x-ray absorption is related to blood flow, 
concentration of the contrast medium, and extraction of the contrast 
medium by interstitial tissue of tumors since no barrier exists. Contrast 
enhancement is thus due to the relative differences in extravascular 
diffusion between normal and abnormal tissue, quite different from that 
in the brain. 
 
The pharmacokinetics of iopamidol in both normal and abnormal tissue 
have been shown to be variable. Contrast enhancement appears to be 
greatest soon after administration of the contrast medium, and 
following intraarterial rather than intravenous administration. Thus, 
greatest enhancement can be detected by a series of consecutive two- 
to three-second scans performed just after injection (within 30 to 90 
seconds), i.e., dynamic computed tomographic imaging. 


 
 
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43 
 


 
 
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44 
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Appendices: 
Appendix A:   
Meal Suggestions the Evening Before and Morning of 18F-FDG PET Scanning13  
 
Permitted Foods  
- 
Chicken, turkey, fish, steak, ham, bacon 
- 
Meat-only sausages, hotdogs (plain, without the bun), hamburgers (plain, 
without the bun or vegetables) 
- 
Fried eggs (prepared without milk or vegetables)  
- 
Water 
Not-Permitted Foods 
- 
Foods containing carbohydrates, sugars, and Splenda (McNeil 
Nutritionals) 
- 
Milk, cheese 
- 
Bread, bagels, cereal, muffins, cookies, crackers, pasta 
- 
Rice, beans 
- 
Peanut butter, nuts 
- 
Fruit, fruit juice, vegetables 
- 
Candy, chewing gum, mints, cough drops 
- 
Alcohol  
- 
Caffeinated foods or beverages (coffee, tea)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Appendix B:  Protocol Evaluation 
1Visits with in +/-  30 days due for unforeseen events. M (month).  Delays in visit will need to be 
discussed and pre-approved with the research team. 
2Baseline: H&P and laboratory studies (see section 2.3) should be completed with in 2 weeks of 
initiating treatment. 
3Within 2 weeks of starting drug the screening process can be completed. 
4 See section Screening Evaluation, E for a list of the screening labs. 
5Concomitant medication review will be performed to update subject medication list. 
6MRI Questionnaire will be completed prior to MRI scan (See Appendix C). 
7See section Safety Measures, 3.2 for list of safety labs. 
8Subjects will be taken off treatment/study after the final visit and referred back to their primary 
physician or have the option to enroll on another protocol if one is available and they meet the 
eligibility criteria. 
Visit number1 
1 
2 
3 
4 
 
5 
6 
78 
 
Screen3 
M0 
M 3 
M 6 
 
M 12 
M 18 
M 24 
Procedure 
 
 
 
 
 
 
 
 
Obtain consent 
X 
 
 
 
 
 
 
 
Enrollment criteria 
X 
 
 
 
 
 
 
 
History & Physical 
X 
 
 
 
 
X 
 
X 
Screen Labs4 
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
Adverse event 
review 
 
X 
X 
X 
 
X 
X 
X 
Concomitant Med. 
Review5 
 
X 
X 
X 
 
X 
X 
X 
Carotid MRI  
 
X 
 
 
 
X 
 
X 
MRI Questionnaire6 
 
X 
 
 
 
X 
 
X 
eGFR 
 
X 
 
 
 
X 
 
X 
CT angiography  
 
X 
 
 
 
 
 
X 
PET Imaging 
Carotid MRI (PET           
            Participants Only) 
Drug Dispensing & 
Dose Adjustment 
 
X 
 
 
X 
 
 
 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Safety Labs7 
Research Blood         
 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 


 
 
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Appendix C:  NCEP standard care guidelines.  
 
 


 
 
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51 
Appendix D: Instructions for pre-study and follow-up Blood tests 
 
 
Blood Studies: 
      
Blood Tube/Comments: 
Destination: 
 
 
 
CBC w/PLT & Diff  
 1 Lavender (3 mL) 
 
Clinical Lab 
 
 
 
 
 
 
 
 
 
Bldg. 10 
 
 
Chemistry  
 
1 Red/Yellow Rim SST (4mL) Clinical Lab 
 
 
 
 
 
 
 
 
 
Bldg. 10 
 
 
 
 
 
 
 
 
 
 
 
  
 
12-HR Fasting Chol   
1 Red/Yellow Rim SST(4mL) Clinical Lab 
 
 
 
 
 
 
 
 
 
Bldg. 10 
 
 
CK  
 
 
1 Red/Yellow Rim SST (4 mL) Clinical Lab 
 
 
 
 
 
 
 
 
 
Bldg. 10 
 
 
hs-CRP 
 
 
1 Red/Yellow Rim SST (4 mL) Clinical Lab 
 
 
 
 
 
 
 
 
 
Bldg. 10 
 
Hepatic Panel 
 
1 Red/Yellow Rim SST (4 mL) Clinical Lab 
 
 
 
 
 
 
 
 
Bldg. 10 
 
Research Blood 
 
2 Red/Yellow Rim SST (8 mL)  Clinical Lab 
 
 
 
 
 
 
 
 
Bldg. 10 
 
 


 
 
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Appendix E:  MRI Safety Questionnaire 
 
 
 


 
 
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Appendix F:  Targeted enrollment table  


 
 
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Appendix G 
 
1) 
Radio and internet PSA text: 
Public Service Announcement IRB App 01-2010 
Plaque 10-CC-XXXX 
___________________________________________________________________ 
 
Clinical Research Trials/Studies Patient Recruitment 
 
“The National Institutes of Health invites you to participate in a study to 
investigate if using Magnetic Resonance Imaging (MRI) is an effective 
method of measuring plaque that builds up inside of arteries in comparison to 
other measurement methods, to estimate your risk of heart disease and 
stroke. Call  
1-866-999-1116, or TTY 1-866-411-1010, for information. Or visit 
http://clinicaltrials.gov .  All study-related tests and treatments are provided at 
no cost. The NIH is a non-profit government agency and part of the 
Department of Health and Human Services.” 
 
This information is time sensitive. Please air before ___________.   
Please contact me (craggka@mail cc.nih.gov or 301-402-8568) prior to airing after this date. 
 
DRAFT: 03/23/2010