Cardiovascular Diseases Clinical Trial
Official title:
AIM HIGH: Niacin Plus Statin to Prevent Vascular Events
The purpose of this study is to determine whether raising "good cholesterol" with a drug based on the vitamin niacin, while lowering "bad cholesterol" with a statin drug, can prevent more heart disease than the statin alone.
BACKGROUND:
Coronary heart disease (CHD) remains the leading cause of death and disability in the
Western world, with approximately 12.6 million individuals in the United States having a
history of myocardial infarction (MI), angina, or both. There is mounting evidence that
"conventional" therapies aimed at traditional risk factors have not optimized clinical
outcomes. For example, in the Heart Protection Study with 20,536 subjects, the 5-year risk
of a first major vascular event (nonfatal MI or CHD death, stroke, or coronary or
noncoronary revascularization) among placebo-treated patients was 25%. Treatment with
simvastatin reduced this risk to 20% over 5 years, which would project out to a 10-year risk
of 40%. (The National Cholesterol Education Program Adult Treatment Panel III considers
"high risk" or CHD equivalent a 10-year risk of an event greater than 20%.) Even among
patients entering the study with baseline low density lipoprotein cholesterol (LDL-C)
already near or at goal (i.e., LDL-C less than 116 mg/dL) and who achieved a mean on-trial
LDL-C of 70 mg/dL with simvastatin, the 5-year risk of an event was still 18% (projecting to
a 10-year risk of 36%). This residual and unacceptably high risk is likely due to the
increasing prevalence of obesity, type II diabetes mellitus, and the metabolic syndrome.
These disorders are typically accompanied by a constellation of abnormalities that include
impaired glycemic control, hypertension, procoagulant and inflammatory states, and
atherogenic dyslipidemia. The latter includes a wide spectrum of lipid abnormalities (low
HDL-C, high triglycerides and triglyceride-rich remnant lipoproteins, and a preponderance of
small dense, highly-oxidizable LDL particles).
Conventional LDL-C-focused therapies are not effective in targeting this type of
dyslipidemia. Evidence that therapy directed at atherogenic dyslipidemia among patients with
CHD can lower outcomes was shown with gemfibrozil in the VA-HIT trial, which showed a 22 to
24% cardiovascular (CV) event reduction by raising HDL-C (by an average of 6%) and lowering
triglycerides (by an average of 31%). Niacin is an even more effective agent for
simultaneously raising HDL-C and lowering triglycerides and levels of small dense LDL, and
holds the most promise among existing therapies for substantial risk reduction in this
population when added to a statin. This was demonstrated in the HDL Atherosclerosis
Treatment Study (HATS) trial in which atherosclerosis progression was virtually halted and
CV events were reduced by 60 to 90% using combined niacin plus statin therapy.
DESIGN NARRATIVE:
AIM-HIGH is a multicenter, randomized, double-blind, parallel-group, controlled clinical
trial designed to test whether the drug combination of extended release niacin plus
simvastatin is superior to simvastatin alone, at comparable levels of on-treatment LDL-C,
for delaying the time to a first major CV disease outcome over a 4-year median follow-up in
patients with atherogenic dyslipidemia. Prior clinical trials have found only 25 to 35% CV
risk reduction using statin monotherapy (i.e., event rate 2/3 to 3/4 of placebo rate). The
study is needed to confirm whether statin-niacin combination therapy, designed to target a
wider spectrum of dyslipidemic factors in addition to LDL-C, will provide a more substantial
(greater than 50%) reduction of CV events. Epidemiologic studies confirm the high prevalence
of atherogenic dyslipidemia and its impact on CV event rates. Preliminary clinical trials
suggest that targeting these factors with dyslipidemic therapy will reduce CV events. The
study will enroll an estimated 3,300 men and women more than 45 years old at high risk of
recurrent CV events by virtue of having established CV disease together with the two
dyslipidemic elements of metabolic syndrome: low HDL-cholesterol (HDL-C) (less than or equal
to 40 mg/dl) and high triglycerides (TG) (greater than or equal to 150 mg/dl). The study
specifically aims to test this hypothesis for the primary composite clinical end point of
CHD death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome with
objective evidence of ischemia (troponin-positive or ST-segment deviation), or
symptom-driven coronary or cerebral revascularization. Secondary end points include the
composite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for high-risk acute
coronary syndrome; the composite of CHD death, nonfatal MI or ischemic stroke; and
cardiovascular mortality.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention
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