Objectives

The AIM-HIGH study tested the hypothesis that patients with atherosclerotic cardiovascular disease optimally treated on a statin but with residual atherogenic dyslipidemia will benefit from the addition of extended release niacin (Niaspan, AbbVie, Inc.) with fewer cardiovascular events compared with placebo.

Background

Coronary heart disease (CHD) remains the leading cause of death and disability in the U.S. and the Western world. Dyslipidemia is one of the major modifiable risk factors of atherosclerosis. Elevated LDL cholesterol levels are an established predictor of CHD risk, while elevated levels of HDL cholesterol inhibit plaque formation and have a strong association with lower rates of incident CHD events. An increasingly common dyslipidemia seen among patients with established vascular disease is atherogenic dyslipidemia (low levels of HDL cholesterol, elevated triglyceride levels, and small, dense particles of LDL cholesterol) which presents an increased risk for CHD and cardiovascular events. Statin therapy has been shown to reduce LDL cholesterol levels and the risk of cardiovascular events. However, substantial residual risk persists despite the achievement of target LDL cholesterol levels.

Participants

Eligible patients included men and women at least 45 years old with established cardiovascular disease, defined as documented CHD, cerebrovascular or carotid disease, or peripheral arterial disease. Patients also must have had atherogenic dyslipidemia, defined as low baseline levels of HDL cholesterol (≤40 mg/dL for men, or ≤50 mg/dL for women), elevated triglyceride levels (150 to 400 mg/dL), and LDL cholesterol levels less than or equal to 180 mg/dL if not taking a statin at study entry. For patients entering the trial already on a statin, the upper limit for LDL cholesterol was adjusted according to the specific statin and dose, HDL cholesterol must have been ≤42 mg/dL for men or ≤53 mg/dL for women, and triglyceride levels must have been 100 to 400 mg/dL.

Design

Eligible, consenting patients entered a 4-to-8-week open-label phase during which they received simvastatin at a dose of 40 mg per day, plus niacin at doses that were increased weekly from 500 mg per day to 2000 mg per day. Participants tolerating at least 1500 mg of niacin per day were randomly assigned, in a 1:1 ratio, to extended release niacin or matching placebo. Participants in the niacin group received niacin at a dose of 1500 to 2000 mg per day plus simvastatin. Participants in the placebo group received simvastatin plus a matching placebo that contained a small dose (50 mg) of immediate-release niacin, added to simulate the flushing response to niacin. In both groups, study participants received simvastatin at a dose of 40 to 80 mg per day, plus ezetimibe at a dose of 10 mg per day if needed, to maintain an LDL cholesterol level of 40 to 80 mg/dL.

Results

The primary endpoint was time to occurrence of the first of the following: CHD death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. Double-blind therapy was ended early in 2011 after it was determined that extended release niacin was unlikely to have significant benefit on the primary endpoint. Subjects were followed for an additional 18 months during which time lipid treatment was managed by the participant’s personal physician.

Conclusions

Among patients with atherosclerotic cardiovascular disease and low levels of HDL cholesterol, there was no incremental clinical benefit from the addition of niacin to intensive statin therapy during a 36-month follow-up period, despite significant improvements in HDL cholesterol.

N Engl J Med. 2011 Dec 15;365(24):2255-67.

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