Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT00307307 |
| Other study ID # |
CARMA |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
March 24, 2006 |
| Last updated |
May 18, 2006 |
| Start date |
January 2000 |
| Est. completion date |
September 2005 |
Study information
| Verified date |
March 2006 |
| Source |
University of Pennsylvania |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
United States: Institutional Review Board |
| Study type |
Interventional
|
Clinical Trial Summary
The primary objective of this randomized, double blind, placebo controlled pilot study is to
determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase inhibitor –
simvastatin) or increasing HDL cholesterol (Niaspan) will induce regression of carotid
atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at
baseline will be compared to that after 6 and 12 months of therapy and changes in MR
characteristics will be compared to changes in lipoprotein parameters and urinary
isoprostanes. The effect of moderate LDL reduction, aggressive LDL reduction and the
combination of aggressive LDL reduction and HDL elevation on MRI plaque characteristics will
be compared by randomly assigning subjects (n=69) with carotid disease (>30% stenosis by
ultrasound criteria) to one of three treatment arms;
1. Simvastatin 20 mg daily and placebo Niaspan (n=23)
2. Simvastatin 80 mg daily and placebo Niaspan (n=23)
3. Simvastatin 20 mg daily and active Niaspan (n=23) Treatment group 2 and 3 will have
roughly equivalent LDL lowering because of the synergistic LDL lowering effect of the
combination of simvastatin and Niaspan.
Description:
FULL PROTOCOL
1.0 SYNOPSIS The primary objective of this randomized, double blind, placebo controlled
pilot study is to determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase
inhibitor – simvastatin) or increasing HDL cholesterol (Niaspan) will induce regression of
carotid atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at
baseline will be compared to that after 6 and 12 months of therapy and changes in MR
characteristics will be compared to changes in lipoprotein parameters and urinary
isoprostanes. The effect of moderate LDL reduction, aggressive LDL reduction and the
combination of aggressive LDL reduction and HDL elevation on MRI plaque characteristics will
be compared by randomly assigning subjects (n=69) with carotid disease (>30% stenosis by
ultrasound criteria) to one of three treatment arms;
1. Simvastatin 20 mg daily and placebo Niaspan (n=23)
2. Simvastatin 80 mg daily and placebo Niaspan (n=23)
3. Simvastatin 20 mg daily and active Niaspan (n=23) Treatment group 2 and 3 will have
roughly equivalent LDL lowering because of the synergistic LDL lowering effect of the
combination of simvastatin and Niaspan.
2.0 BACKGROUND Atherosclerotic carotid disease is the largest single etiological factor
known to produce focal cerebral ischemia (1). Only a small percentage of patients with
asymptomatic carotid atherosclerosis develop stroke but the majority of these have have no
warning symptoms. The degree of internal carotid stenosis at ultrasound angiography, the
commonest methods of assessing the risk of stroke, are poor predictors of stroke in patients
with asymptomatic carotid atherosclerosis (2) and clinical risk factors have a high
prevalence but a low relative risk of stroke in these patients. Most plaque rupture occurs
in unstable lipid rich plaques with thin fibrous caps weakened by inflammation and apoptosis
(3). Thus, the morphological characteristics of carotid plaques may provide important
information regarding ischemic risk of carotid lesions. We, and others, are using high
resolution MR imaging (4-6) to differentiate carotid plaque elements such as the lipid core,
the fibrous cap and hemorrhage with the ultimate goal of determining the ischemic potential
of carotid atherosclerotic plaques.
Lipid lowering therapy with statins is considered standard treatment for patients with
atherosclerosis and hypercholesterolemia (7-9). Statin therapy reduces LDL cholesterol
levels, cardiovascular events and death and retards the progression of atherosclerosis as
assessed by noninvasive intima-media thickness (IMT) on carotid ultrasound (10). However,
the optimal degree of LDL cholesterol lowering with statins in patients with atherosclerosis
remains unclear (7,8) – thus there are a number of ongoing large clinical trials comparing
the effect of low dose to high doses of statins on cardiovascular effects in patients with
coronary atherosclerosis (eg “Treatment to New Targets”). Low HDL cholesterol is an
independent risk factor for the development and progression of atherosclerosis (11). Niacin
is one of a few effective therapies that significantly elevates HDL levels and was shown to
reduce cardiovascular events in patients with known coronary atherosclerosis prior to the
development of statin drugs (12,13). Increased HDL is thought to promote reverse cholesterol
transport from the peripheral tissues including atherosclerotic plaque (14-16). Presently,
niacin is not considered standard therapy in patients with known atherosclerosis. Niaspan is
a new controlled-release form of niacin that is administered once daily, is better tolerated
than crystalline niacin which is given 3 times a day (17,18). It has been shown to result in
a greater than 30% increase in HDL cholesterol and preliminary data suggest that it is safe
and effective and not associated with hepatotoxicity (19). In the proposed study patients
(n=60) with carotid disease (>30% stenosis by ultrasound criteria) will be randomly assigned
to one of three treatment arms;
1. Simvastatin 20 mg daily and placebo Niaspan (n=23)
2. Simvastatin 80 mg daily and placebo Niaspan (n=23)
3. Simvastatin 20 mg daily and active Niaspan (n=23) Thus, the effect of Simvastatin 10 mg
(moderate LDL reduction), Simvastatin 80 mg (aggressive LDL reduction) and the
combination of Simvastatin and Niaspan (aggressive LDL reduction and HDL elevation) on
MRI plaque characteristics will be compared.
3.0 OBJECTIVES
The primary objective of this randomized, double blind, placebo controlled pilot study is to
determine if therapies aimed at lowering LDL cholesterol (HMGCoA reductase inhibitors –
statins) or increasing HDL cholesterol (Niaspan) will induce regression of carotid
atherosclerotic plaque in vivo using MRI imaging techniques. MR plaque morphology at
baseline will be compared to that after 6 and 12 months of therapy and changes in MR
characteristics will be compared to changes in lipoprotein parameters and urinary
isoprostanes.
3.1 Primary End-Point The primary end-point is the change in carotid plaque volume at MRI
after 12 months of treatment.
3.2 Secondary End-Points
1. – change in carotid plaque lipid content at MRI after 12 months
2. – change in lipid parameters after 12 months
3. – change in urinary isoprostane excretion after 12 months
4.0 STUDY DESIGN
4.1 Description
This study will be randomized, double-blind and placebo controlled. Sixty patients will be
randomly assigned to (1) Simvastatin 20 mg and placebo Niaspan, (2) Simvastatin 80 mg and
placebo Niaspan or (3) Simvastatin 20 mg and active Niaspan. The study will involve 6
outpatient visits to the General Clinical Research Center (GCRC) at the Hospital of the
University of Pennsylvania. Each visit will last approximately 2 hours.
4.2 Number of Subjects
Sixty nine (69) subjects with known carotid atherosclerosis will be investigated.
5.0 STUDY POPULATION
Source of subjects
Subjects with carotid disease, identified on (1) routine carotid ultrasound examinations at
the vascular laboratories of the University of Pennsylvania Health System and VA Medical
Center, and (2) through local advertisement will be invited to participate in the study.
Subjects will be contacted by letter inviting them to participate in the study. Subjects
will be screened according to the following inclusion and exclusion criteria;
Inclusion Criteria Age >18 and <90 years Capacity for giving written informed consent
Carotid stenosis of >30% by ultrasound criteria LDL cholesterol level of >100mg/dl Systolic
BP < 170 and diastolic BP < 100 under resting conditions Negative pregnancy test if female
of child-bearing potential
Exclusion criteria Recent (< 3 months) history of stroke, transient ischemic attack,
myocardial infarction, unstable angina or critical limb ischemia, Contraindications to MRI
(claustrophobia, presence of pacemakers, defibrillators, metal foreign bodies), History of
side effect/adverse reaction on HMGCoA reductase inhibitor, Niaspan or niacin, Poorly
controlled diabetes (HbA1c >8%), History of myositis, liver disease or abnormal LFTs, Need
for combination therapy for the control of severe hyperlipidemia, Abnormal LFT (>2 fold
upper limit normal), Active infection or malignancy.
6.0 STUDY PROCEDURES The study will involve 6 outpatient visits to the General Clinical
Research Center (GCRC) at the Hospital of the University of Pennsylvania. Each visit will
last approximately 2 hours.
6.1 Pre-treatment Period All subjects will be asked to come to GCRC for a screening visit.
During this visit, a complete medical history and physical examination will be performed.
Dosage of all chronic medication will be recorded. Supine resting blood pressure, an
electrocardiogram and the following fasting routine laboratory studies will be performed;
Hematology; hemoglobin, hematocrit, MCV, white blood count and platelet count Blood
chemistries; sodium, potassium, chloride, creatinine, fasting glucose, albumin, alkaline
phosphatase, total bilirubin, AST, ALT, uric acid total cholesterol, LDL, HDL, triglycerides
lipoprotein (a) and HbA1c.
Urinalysis Urinary HCG - for women of child bearing potential. Eligible subjects will
undergo a full dietary assessment by the GCRC research dietician using a quantitative
questionnaire. Subjects will be instructed to comply with recommended AHA dietary guidelines
so that dietary intake of macronutrients including fat and cholesterol will be similar
across all subjects. Dietary compliance will be monitored at baseline and each study visit
by 24-hour recall of dietary intake. The Dietary Analysis System (DIETSYS) will be used to
analyze the food frequency questionnaires and the Food Processor Plus (ver 6.0) will be used
to analyze dietary recalls.
6.2 Concurrent Treatment The use of most concurrent medications will not be restricted
during the study period. Indeed, aspirin use and antihypertensive therapies will be
encouraged when appropriate. Lipid lowering medications, other than those in the study will
be stopped prior to randomization. For example all HMGCoA reductase inhibitors will be
replaced by simvastatin at the time of randomization.
6.3 Treatment Period Eligible subjects will be asked to collect a 12-hour urine sample prior
to randomization and bring them to the GCRC on the morning of randomization where they will
be processed and stored until analysis. Baseline blood samples will be collected for
hematology, chemistry and lipoprotein analysis as per screening. Subjects will undergo micro
MRI scans of the carotid arteries in the MRI center adjacent to the GCRC. A subset of
volunteers (n=10) will be asked to undergo a second baseline MRI scan within a week of the
first scan in order to determine the reproducibility of the quantitative MRI technique.
Subjects will then be randomized in a double blind manner to (1) Simvastatin 20 mg and
placebo Niaspan, (2) Simvastatin 80 mg and placebo Niaspan or (3) Simvastatin 20 mg and
active Niaspan. Simvastatin tablets will be provided by Merck Pharmaceuticals, the
manufacturer of Simvastatin. Niaspan tablets (500mg) and matching placebo will be provided
by KOS, the company that manufactures Niaspan. Niaspan will be titrated according to
clinical guidelines – 500 mg at bedtime for 1 month, 1000 mg at bedtime for the next month
and finally 2000 mg at bedtime for the rest of the study. At the randomization visit, these
specific instructions for titration of Niaspan or placebo (given in matching tablets in an
identical way) will be discussed and given to each subject with a one-month supply of study
drug.
Both Niaspan (KOS Pharmaceuticals) and simvastatin (Zocor; Merck Pharmaceuticals) are
commercially available drugs that are FDA approved for management of hyperlipidemia at the
doses, formulation and route of administration proposed in this study.
Return visits will be scheduled for 1, 3, 6 and 12 months. At each of these visits history,
physical exam and blood testing (hematology, chemistry, fasting lipoproteins) will be
undertaken. In addition, urine collections and MRI studies will be performed at 6 and 12
months. Known adverse effects, such as flushing and muscle cramps will be screened for at
each visit. Subjects will be discontinued from the study for the following reasons;
1. intolerable side effects from the study medications
2. increase in either ALT or AST greater than 3 times upper limit of normal
3. HbA1c>9%
4. uric acid >11.0
5. pregnancy
Eligible subjects will be asked to increase study medication to 2000mg daily at bedtime
after the second month. Every attempt will be made to titrate the Niaspan/placebo to 2000mg
per day, but if this is not possible the subject will be maintained on the maximal
achievable dose. The duration of the study is 12 months. All assessments will be made by
personnel blinded to the study treatment.
6.4 Duration of the Study The duration of the entire study will be approximately 18 months.
Actual study drug treatment will be of 12 months duration. Each subject will undergo
screening approximately 2 weeks prior to randomization and it is anticipated that subjects
will be enrolled over a 6 month period.
6.5 Premature Withdrawal from the Study
A volunteer may be withdrawn from the trial for the following reasons:
- Any adverse event thought to warrant withdrawal by the investigator,
- Poor compliance thought to warrant withdrawal by the investigator,
- Volunteer’s desire to withdraw from the study at any time,
- Protocol or entry criteria violation,
- Pregnancy.
The reasons for withdrawal and the final outcome in cases of adverse events will be
documented on the Case Report Form. Subjects who do not complete the study will be replaced.
7.0 EFFICACY ASSESSMENT
7.0 Variables to be measured for Efficacy Assessment Magnetic Resonance Imaging of Carotid
Atherosclerotic Plaques: A variety of MRI techniques have been optimized to permit
sufficient resolution to determine size and composition of atherosclerotic plaque. These
include "black-blood" imaging techniques, fast spin echo sequences, and fat suppression
techniques in addition to customized coils (4-6). Customized surface coils will be
constructed to further improve the signal-to-noise ratio. While the coils and some of the
sequences are not FDA approved as they are custom built, they all fall under the category of
“non-significant risk devices”. These techniques have already been established for this
purpose at the MRI center at the Hospital of the University of Pennsylvania. The imaging
protocol consists of a combination of black blood (fast spin echo and double inversion
recovery fast spin echo sequences) and bright blood imaging (time-of-flight MRA sequence) to
achieve optimal contrast between the arterial lumen and the vessel wall. Specifically, the
following sequences are obtained: (1) 3D time of flight (TOF) MRA of the carotid
bifurcation; (2) axial T1-weighted fast spin echo; (3) axial proton density-weighted
weighted double inversion recovery fast spin echo (DIR-FSE) through plaque; and (4) axial
T2-weighted weighted DIR-FSE through plaque. Total plaque volume will be quantified as
follows;
Plaque volume = (computer assisted calculation of region of interest-ROI) x (slice
thickness) x (no. of slices).
Plaque composition will be estimated using established imaging criteria for the 4 image
contrast weightings (Table 1).
Table 1 Criteria used for identification of plaque constituents. TOF T1-W PD-W T2-W
Calcification Low Low Low Low Hemorrhage High High/Moderate Variable Variable Lipid core
Moderate High High Variable Fibrous cap Moderate/Low Moderate High Variable Note: Intensity
descriptors are relative to intensity of sternocleidomastoid muscle.
Lipoprotein Determination: Total cholesterol, LDL cholesterol, HDL cholesterol, lipoprotein
(a) and triglyceride levels will be determined by standardized techniques in the routine
chemistry laboratory of the Hospital of the University of Pennsylvania.
Urinary Isoprostanes: Urinary isoprostanes will be measured by mass spectrometry / gas
chromatography (GC / MS) as previously described by the PI (20). Following the addition of a
deuterated isoprostane internal standard, urine samples are extracted from the aqueous
matrix by solid phase extraction techniques, purified by thin layer chromatography,
derivatized, and analyzed by GC / MS in the negative ion chemical ionization (NICI) mode.
Quantification is accomplished by taking the ratio of the area under the peak of the ion
representing the endogenous compound to that of the internal standard.All subjects who
complete the study will be considered evaluable for efficacy assessment.
7.2 Criteria for Evaluability of Efficacy Assessment
All subjects who complete the study will be considered evaluable for efficacy assessment.
8.0 SAFETY ASSESSMENT
8.1 Variables to be Measured for Safety Assessment
Safety measures to be monitored include
1. symptoms (flushing, abdominal pain, tiredness)
2. transaminases
3. HbA1c
4. uric acid
8.2 Criteria for Evaluability of Safety Assessment
All subjects entered into the trial will be considered evaluable for safety assessment.
9.0 STATISTICAL CONSIDERATIONS
There is currently no data available on the effect of therapies on carotid atherosclerotic
plaque morphology using MRI on which to base sample size estimations. Therefore, sample
sizes are based on the desire to acquire pilot data to allow the determination of the actual
numbers required for a study examining both MR characteristics and clinical endpoints. A
sample size of 69 (23 subjects per arm) will provide 80% power to detect the hypothesized
difference (15%) in the primary endpoint (plaque volume) between 2 different treatment arms
at an alpha of 0.05. The number of subjects needed for future full-scale clinical studies
will be dependent on the coefficient of variation of repeated baseline quantitative MRI
scans and the change in plaque volume (primary end-point) following an intervention. These
parameters will be defined by the proposed pilot study.
10.0 DATA COLLECTION, MONITORING AND AE REPORTING
10.1 Case Report Forms
Case Report Forms (CRFs) will be provided for each subject. Subjects must not be identified
by name on any study documents. Subjects will be identified by the Patient Identification
Number (PIN) and Study Identification Number (SID). All data on the CRF will be legibly
recorded in black ink or typed. Corrections will be made by striking the incorrect entry
with a single line through it and then adding the correct information adjacent to it. The
corrections will be initialed and dated by the investigator or designated qualified
individual. Any requested information that is not obtained as specified in the protocol will
be indicated on the CRFs as “not done” (ND) or “not applicable” (NA).
10.2 Data Management
The CRF design and data management will be performed by the PI and research assistants.
10.3 Monitoring
The PI will review the research records for accuracy, completeness and legibility. The
investigator or designated qualified individual will make study documents (eg consent forms,
drug distribution forms, case report forms) and pertinent hospital or clinic records
available for inspection by the Food and Drug Administration (FDA) for conformation of the
data.
10.4 Adverse Experience (AE) Reporting
Adverse Experiences (AEs) will be monitored throughout the study and such events will be
recorded on the Adverse Experience Case Report Forms. An AE is defined as any unfavorable
and unintended change in the structure, function or chemistry of the body temporally
associated with the use of the study medication, whether or not considered related to the
use of the product. The AEs will be graded on a three-point scale (mild, moderate severe)
and a drug relationship assigned.
Any serious or unexpected adverse events will be reported within 24 hours to the FDA and the
IRB of the University of Pennsylvania. Adverse events are defined as serious when they are
fatal, life-threatening or result in in-patient hospitalization or prolongation of
hospitalization. In addition the occurrence of malignancy is always considered serious
adverse advents. Adverse events are considered unexpected if their occurrence, or severity
or frequency have not been previously reported in concomitance with Niaspan or HMGCoA
reductase inhibitor therapy.
11.0 ETHICAL CONSIDERATIONS
11.1 Institutional Review Board (IRB)
The study protocol will be reviewed by the committee on Studies involving Human Beings at
the University of Pennsylvania. A copy of the letter of approval and correspondence with the
IRB will be retained by the investigators.
11.2 Informed Consent
Written informed consent will be obtained from every volunteer participating in the study
after adequate explanation of the object of the study and possibly adverse effects of the
drug treatment.
11.3 Subject Confidentiality
The medical information gathered during this study will be treated confidentially except as
may be required by law. Regulatory authorities, including the US Food and Drug
Administration, might review the medical records to verify the accuracy of the information
collected. Subjects will not be identified by name on any study documents and, if the
results are published the subjects’ identity will not be disclosed.
REFERENCES
1. Gelabert HA and Moore WS. Carotid endarterectomy: current status. Curr Prob Surg 1991;
XXVIII: 187-262.
2. Moneta GL, Taylor DC, Zierler RE, Kazmers A, Beach K and Stradness DE. Asymptomatic
high grade internal carotid carotid artery stenosis: is stratification according to
risk factors or duples spectral analysis possible. J Vasc Surg 1989; 10: 475.
3. Libby P, Li H. Vascular cell adhesion molecule-1 and smooth muscle cell activation
during atherogenesis. J Clin Invest 1993; 92: 538-539
4. Skinner MP, Yuan C, Mitsumori L, Hayes CE, Raines EW, Nelson JA, Ross R. Serial
magnetic-resonance imaging of experimental atherosclerosis detects lesion fine
structure, progression and complications in vivo. Nature Medicine 1995; 1: 69-73.
5. Toussaint J-F, Southern JF, Fuster V, Kantor HL. T2-weighted contrast for NMR
characterization of human atherosclerosis. Arterioscler Thromb Vasc Biol 1995; 15:
1533-42.
6. Toussaint J-F, LaMuraglia GM, Southern JF, Fuster V, Kantor HL. Magnetic resonance
images lipid, fibrous, calcified hemorrhagic and thrombotic components of human
atherosclerosis in vivo. Circulation 1996; 94: 932-938.
7. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering
in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival
Study (4S). Lancet 1994; 344: 1383-89.
8. Ridker, P. M., N. Rifai, M. A. Pfeffer, F. M. Sacks, L. A. Moye, S. Goldman, G. C.
Flaker, and E. Braunwald. Inflammation, pravastatin, and the risk of coronary events
after myocardial infraction in patients with average cholesterol levels. Cholesterol
and recurrents events (CARE) investigatiors . Circulation 1998; 98:839-844.
9. Jukema JW, Bruschke AVG, van Boven AJ et al; on behalf of the REGRESS Study Group.
Effects of lipid lowering by pravastatin on progression and regression of coronary
artery disease in symptomatic men with normal to moderately elevated serum cholesterol
levels. The regression growth evaluation statin study (REGRESS). Circulation 1995; 91:
2528-40.
10. Crouse JR, Byington RP, Bond MG, Espeland MA, Craven TE, Sprinkle JW, McGovern ME,
Furberg CD. Pravastatin, lipids and atherosclerosis in the carotid arteries (PLAC-II).
Am J Cardiol 1995;75: 455-9.
11. Vega, G. L. and S. M. Grundy. Hypoalphalipoproteinemia (low high density lipoprotein)
as a risk factor for coronary heart disease. Curr. Opin. Lipidol. 1996; 7:209-216.
12. Canner, P. L., K. G. Berge, N. K. Wenger, J. Stamler, L. Friedman, R. J. Prineas, and
W. Friedwald. Fifteen year mortality in Coronary Drug Project patients: Long term
benefit with niacin. J Am Coll Cardiol 1986; 8:1245-1255.
13. Blankenhorn DH, Nessim SA, Johnson RL, Sanmarco ME, Azen SP, Cashin-Hemphill L.
Beneficial effects of colestipol-niacin therapy on coronary atherosclerosis and
coronary venous bypass grafts. JAMA 1987; 257: 3233-3240.
14. Reichl, D. and N. E. Miller. Pathophysiology of reverse cholesterol transport. Insights
from inherited disorders of lipoprotein metabolism. Arteriosclerosis 1989; 9: 785-797.
15. Plump AS, Scott CJ, Breslow JL. Human apolipoprotein A-I gene expression increases high
density lipoprotein and suppresses atherosclerosis in the apolipoprotein E-deficient
mouse. Proc Natl Acad Science 1994; 91: 9607-9611.
16. Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion
after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol
transport in humans. Circulation 1999; 100: 594-598.
17. Rosenson, R. S. 1993. Low levels of high-density lipoprotein cholesterol
(hypoalphalipoproteinemia): an approach to management. Arch Intern Med 1993;
153:1528-1538.
18. Alderman JD, Pasternak RC, Sacks FM, Smith HS, Monrad ES, Grossman W. Effect of a
modified, well tolerated niacin regimen on serum total cholesterol, high density
lipoprotein and the cholesterol to high density lipoprotein ratio. Am J Cardiol 1989;
64: 725-729.
19. Morgan, J. M., D. M. Capuzzi, J. R. Guyton, R. M. Centor, R. Goldberg, D. C. Robbins,
D. Dipette, S. Jenkins, and S. Marcovina. Treatment effect of Niaspan, a
controlled-release niacin, in patients with hypercholesterolemia: a placebo-controlled
trial. J Cardiovasc Pharm Ther 1996; 1:195-202.
20. Reilly MP, Pratico D, Delanty N, DiMinno G, Tremoli E, Rader D, Kapoor S, Lawson JA,
Rokach J, FitzGerald GA. Increased biosynthesis of distinct F2-isoprostanes in
hypercholesterolemia. Circulation 1998; 98: 2822-2828.
