Niacin Plus Statin to Prevent Vascular Events

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.

Inclusion Criteria:

- Men and women aged 45 and older with established vascular disease and atherogenic
dyslipidemia

- Established vascular disease defined as one or more of the following: (1) documented
coronary artery disease (CAD); (2) documented cerebrovascular or carotid disease; (3)
documented symptomatic peripheral arterial disease (PAD)

- Atherogenic dyslipidemia defined as: (1) LDL-C of less than or equal to 160 mg/dL
(4.1 mmol/L); (2) HDL-C of less than or equal to 40 mg/dL (1.0 mmol/L) for men or
less than or equal to 50 mg/dL (1.3 mmol/L) for women; (3) TG greater than or equal
to 150 mg/dL (1.7 mmol/L) and less than or equal to 400 mg/dL (4.5 mmol/L)

- For patients entering the trial on a statin: (1) the upper limit for LDL-C is
adjusted according to the specific statin and statin dose; (2) HDL-C of less than or
equal to 42 mg/dL (1.1 mmol/L) for men or less than or equal to 53 mg/dL (1.4 mmol/L)
for women; (3) TG greater than or equal to 125 mg/dL (1.4 mmol/L) and less than or
equal to 400 mg/DL (4.5 mmol/L)

Exclusion Criteria:

- Coronary artery bypass graft (CABG) surgery within 1 year of planned enrollment
(run-in phase)

- Percutaneous coronary intervention (PCI) within 4 weeks of planned enrollment (run-in
phase)

- Hospitalization for acute coronary syndrome and discharge within 4 weeks of planned
enrollment (run-in phase)

- Fasting glucose greater than 180 mg/dL (10 mmol/L) or hemoglobin A1C greater than 9%

- For patients with diabetes, inability or refusal to use a glucometer for home
monitoring of blood glucose

- Concomitant use of drugs with a high probability of increasing the risk for
hepatotoxicity or myopathy, such as those predominantly metabolized by cytochrome
P450 system 3A4, including but not limited to cyclosporine, gemfibrozil, fenofibrate,
itraconazole, ketoconazole, HIV protease inhibitors, nefazodone, verapamil,
amiodarone; lipid-lowering drugs (other than the investigational drugs) such as
statins, bile-acid sequestrants, cholesterol absorption inhibitors (e.g., ezetimibe),
fibrates or high-dose, antioxidant vitamins (vitamins C, E, or beta carotene) that
can interfere with the HDL-raising effect of niacin