Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 2 - ARBITER 2

Description:

ARBITER-2 was a randomized, double-blind, single-center secondary prevention trial of extended-release niacin versus placebo in patients with controlled low-density lipoprotein (LDL) cholesterol levels already taking statin therapy.

Hypothesis:

The addition of niacin (administered as an extended release formulation) to statin therapy would result in less of a change in carotid intimal medial thickness (IMT) than placebo control in patients with controlled LDL cholesterol levels.

Study Design

Study Design:

Patients Enrolled: 149
Mean Follow Up: One year
Mean Patient Age: Mean 67 years
Female: 11

Patient Populations:

Men and women >30 years old with known coronary vascular disease. All subjects were required to be currently treated with a statin drug, with a documented LDL cholesterol <130 mg/dl and HDL <45 mg/dl.

Exclusions:

Known intolerance to niacin or a history of liver disease or abnormal liver associated enzymes (>3 times the upper laboratory reference value)

Primary Endpoints:

Change in mean common carotid IMT after one year, assessed within each study group

Secondary Endpoints:

Changes in serum lipid concentrations; adverse events including liver-associated enzyme elevations; and composite of clinical cardiovascular events including any hospitalization for an acute coronary syndrome, stroke, arterial revascularization procedure, or sudden cardiac death

Drug/Procedures Used:

Randomization to blinded placebo control or extended-release niacin at 500 mg/day for one month with uptitration to 1 g/day for another 11 months

Concomitant Medications:

Continuation of aspirin and statin therapy. Discontinuation of antioxidant medications (vitamin E and C) was strongly encouraged.

Principal Findings:

A total of 167 patients were enrolled, and all patients had a history of coronary artery disease and were taking concomitant statin therapy. The baseline characteristics of both study groups were similar, and the mean baseline lipid concentrations were 157 mg/dl for total cholesterol, 89 mg/dl for LDL, and 40 mg/dl for high-density lipoprotein (HDL). Of the 167 patients randomized, 89% (149) completed the 12-month follow-up period.

At 12 months, in the placebo arm, the mean LDL slightly decreased from 91 to 86 mg/dl, while the HDL remained at 40 mg/dl, and the triglyceride level slightly decreased from 172 mg/dl to 164 mg/dl (all p=NS for change within the group). In the niacin arm, the mean LDL slightly decreased from 87 mg/dl to 85 mg/dl, while the HDL rose from 39 mg/dl to 47 mg/dl (p<0.001), and the triglyceride level fell from 154 mg/dl to 134 mg/dl (p=0.009). Comparing the 12-month lipid concentrations between the two study groups, HDL was higher and triglycerides were lower in the niacin arm than in the placebo group (p=0.003 and p=0.03, respectively); all other comparisons between the two study arms were not significantly different.

The increase in carotid IMT was 0.014 mm in the niacin group and 0.044 mm in the placebo group (p=0.08). Within each group, the increase in carotid IMT at 12 months was not significant when compared to baseline in the niacin group (p=0.23), whereas it was significantly greater at 12 months compared to baseline in the placebo group (p<0.001). Clinical cardiovascular events occurred in three patients treated with niacin and seven patients treated with placebo (3.8% vs. 9.6%, p=0.2). The rate of study drug discontinuation was similar in both groups, although skin flushing was far more common among patients treated with niacin (69.2% vs. 12.7%, p<0.001).

Interpretation:

In this randomized, placebo-controlled, single-center study of niacin therapy in addition to statin therapy among patients with controlled LDL cholesterol levels and HDL cholesterol levels <45 mg/dl, niacin further improved lipid profiles and slowed progression of carotid IMT at 12 months compared to placebo. This study is the first prospective demonstration of an incremental effect of niacin in addition to statin therapy, and these findings are particularly relevant given that the mean baseline LDL level in the study was 89 mg/dl. Despite the frequent side effect of cutaneous flushing, the drug appeared to be well-tolerated, and further prospective studies are warranted to determine whether the effects on lipid profiles and carotid IMT can be translated into improved clinical outcomes.

References:

Presented by Allen J. Taylor at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.

Published online: Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2. A Double-Blind, Placebo-Controlled Study of Extended-Release Niacin on Atherosclerosis Progression in Secondary Prevention Patients Treated With Statins. Circulation 2004:01.CIR.0000148955.19792.8D.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Atherosclerotic Disease (CAD/PAD), Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Cholesterol, Coronary Artery Disease, Pyridinolcarbamate, Secondary Prevention, Hyperlipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Niacin, Hypercholesterolemia, Triglycerides, Tunica Intima


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