This study is being conducted to compare the efficacy, safety, and tolerability of
ezetimibe/simvastatin 10/20 mg when administered daily versus doubling the dose of
simvastatin to 40 mg in patients with hypercholesterolemia and coronary heart disease.
Inclusion Criteria:
- Subjects must have documented coronary heart disease (CHD). For the purposes of this
study, CHD will include one or more of the following features: documented stable
angina (with evidence of ischemia on exercise testing); history of myocardial
infarction; history of percutaneous coronary intervention (primarily PCI with or
without stent placement); symptomatic peripheral vascular disease (claudication);
documented history of atherothrombotic cerebrovascular disease; and/or documented
history of unstable angina or non-Q wave myocardial infarction.
- Subjects must demonstrate their willingness to participate in the study and comply
with its procedures by signing a written informed consent.
- History of myocardial infarction (heart attack).
- Subjects must be >= 18 years and <= 75 years of age.
- Subjects must have an LDL-C concentration >= 2. 6 mmol/L (100 mg/dL) to <= 4. 1 mmol/L
(160 mg/dL) at the time of randomization (Visit 3/Baseline Visit).
- Subjects must have triglyceride concentrations of < 3. 99 mmol/L (350 mg/dL) at (Visit
3 Baseline Visit).
- Subject must be currently taking simvastatin 20 mg daily.
- Subjects must have liver transaminases (ALT, AST) < 50% above the upper limit of
normal, with no active liver disease, and CK (creatine kinase) < 50% above the upper
limit of normal at Visit 3 (Baseline Visit).
- Clinical laboratory tests (complete blood count [CBC], blood chemistries, urinalysis)
must be within normal limits or clinically acceptable to the investigator at Visit 3
(Baseline Visit).
- Subjects must have maintained a cholesterol-lowering diet and exercise program for at
least 4 weeks prior to the study and be willing to continue the same diet and exercise
program during the study.
- Subjects must report a stable weight history for at least 4 weeks prior to entry into
study at Visit 3 (Baseline Visit).
- Women receiving hormonal therapy, including hormone replacement, any estrogen
antagonist/agonist, or oral contraceptives, must have been maintained on a stable dose
and regimen for at least 8 weeks and be willing to continue the same regimen for the
duration of the study.
- Women of childbearing potential (includes women who are less than 1 year
postmenopausal and women who become sexually active) must be using an acceptable
method of birth control (e. g., hormonal contraceptive, medically prescribed
intrauterine device [IUD], condom in combination with spermicide) or be surgically
sterilized (e. g., hysterectomy or tubal ligation).
- Subjects must be free of any clinically significant diseases other than hyperlipidemia
or coronary heart disease that would interfere with study evaluations.
- Subjects must understand and be able to adhere to the dosing and visit schedules, and
must agree to remain on their cholesterol-lowering diet and their exercise regimen for
the duration of the study.
Exclusion Criteria:
- Subjects whose body mass index (BMI = weight [kg]/height2 [m]) is >= 35 kg/m^2 at
Visit 3 (Baseline Visit).
- Subjects who consume > 14 alcoholic drinks per week. (A drink is: a can of beer,
glass of wine, or single measure of spirits).
- Any condition or situation which, in the opinion of the investigator, might pose a
risk to the subject or interfere with participation in the study.
- Women who are pregnant or nursing.
Exclusion Criteria: subjects who have the following medical conditions:
- Congestive heart failure defined by New York Heart Association (NYHA) as Class III or
IV.
- Uncontrolled cardiac arrhythmia.
- Myocardial infarction, acute coronary insufficiency, coronary artery bypass surgery,
or angioplasty within 3 months of Visit 3 (Baseline Visit).
- Unstable or severe peripheral artery disease within 3 months of Visit 3 (Baseline
Visit).
- Newly diagnosed or currently unstable angina pectoris (chest pain).
- Uncontrolled hypertension (treated or untreated) with systolic blood pressure > 160 mm
Hg or diastolic > 100 mm Hg at Visit 3 (Baseline Visit).
- Type I or Type II diabetes mellitus.
- Uncontrolled endocrine or metabolic disease known to influence serum lipids or
lipoproteins, i. e., secondary causes of hyperlipidemia, such as secondary
hypercholesterolemia due to hypothyroidism (thyroid stimulating hormone [TSH] above
upper limit of normal) at Visit 3. Subjects with a history of hypothyroidism who are
on a stable therapy of thyroid hormone replacement for at least 6 weeks are eligible
for enrollment if TSH levels are within normal limits at Visit 3 (Baseline Visit).
- Impaired renal function (creatinine > 2. 0 mg/dL) or nephrotic syndrome at Visit 3
(Baseline Visit).
- Disorders of the hematologic, digestive, or central nervous systems including
cerebrovascular disease and degenerative disease that would limit study evaluation or
participation.
- Known HIV positive.
- Cancer within the past 5 years (except for successfully treated basal and squamous
cell carcinomas).
- History of mental instability, drug/alcohol abuse within the past 5 years, or major
psychiatric illness not adequately controlled and stable on pharmacotherapy.
Exclusion Criteria: subjects who are on any of the following concomitant medications:
- Subjects who have not observed the designated wash-out period for any of the
prohibited medications.
- Subjects who have not stopped taking various prohibited medications for a minimum
period of time before Visit 3, including amiodarone hydrochloride (6 months) and
probucol (12 months).
- Subjects currently consuming large amounts of grapefruit juice (> 1 liter/day).
- Oral corticosteroids, unless used as replacement therapy for pituitary/adrenal disease
and the subject is on a stable regimen for at least 6 weeks prior to Visit 3 (Baseline
Visit).
- Subjects who are currently using cardiovascular medication (e. g. antihypertensive,
antiarrhythmic) and have not been on a stable regimen for at least 6 weeks prior to
Visit 3 (Baseline Visit) and it is expected to change during the study.
- Subjects who are currently using psyllium, other fiber-based laxatives, and/or any
other over-the-counter (OTC) therapy known to affect serum lipid levels (phytosterol
margarine), and have not been on a stable regimen for at least 5 weeks prior to study
entry Visit 3 (Baseline Visit) and who do not agree to remain on this regimen
throughout the study.
- Subject who are currently using orlistat or sibutramine.
- Subjects who are currently using amiodarone hydrochloride.
- Subjects who are currently using danazol.
- Subjects who are currently using coumarin anticoagulants (warfarin).
- Subjects who are using (at the Screening Visit / Visit 1) any statin other than
simvastatin 20 mg, or ezetimibe alone or in combination with any statin (including the
fixed combination with simvastatin).
