Niacin in Patients With Low HDL Cholesterol Levels Receiving Intensive Statin Therapy

Study Questions:

Is extended-release niacin added to simvastatin superior to simvastatin alone for reducing the risk of cardiovascular events?

Methods:

A total of 3,414 patients with established cardiovascular disease (stable coronary, carotid, or peripheral vascular disease) were randomly assigned to receive extended-release niacin, 1500-2000 mg/day, or matching placebo. All patients received simvastatin, 40-80 mg/day and if needed ezetimibe 10 mg/day to maintain the low-density lipoprotein cholesterol (LDL-C) between 40 and 80 mg/dl. Eligible patients had a baseline low high-density lipoprotein cholesterol (HDL-C) (<40 mg/dl for men and <50 mg/dl for women), triglycerides 150-400 mg/dl, and LDL-C <180 mg/dl, if not on a statin. Primary endpoint was the composite of the first event of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for an acute coronary syndrome, or symptom-driven coronary or cerebral revascularization.

Results:

At baseline, mean age was 64 years, 85% were male, 71.4% had hypertension, and 33.9% diabetes. Cardiovascular history included a myocardial infarction in 56%, coronary artery bypass grafting in 35%, percutaneous coronary intervention in 61%, and pulmonary vascular obstructive disease in 13.6%. Niacin was stopped in 25% of patients and placebo (containing 50 mg of niacin) was stopped in 20.1% (p < 0.001). Significantly more patients in the placebo group were taking simvastatin 80 mg/day (24.7% vs. 17.5%, p = 0.02) and ezetamibe (21.5% vs. 9.5%, p < 0.001). The trial was stopped after a mean follow-up period of 3 years due to lack of efficacy. At 2 years, niacin therapy was associated with an increase in median HDL-C from 35 mg/dl to 42 mg/dl, decrease in triglycerides from 164 mg/dl to 122 mg/dl, and decrease in LDL-C from 74 mg/dl to 62 mg/dl. At 1 year, niacin was associated with an increase in apolipoprotein A-1 from 122 mg/dl to 131 mg/dl, reduction in apo B from 81 mg/dl to 70 mg/dl, and decrease in Lp(a) from 36 mg/dl to 27.1 mg/dl. The primary endpoint occurred in 16.4% in the niacin group and 16.2% in the placebo group (hazard ratio, 1.02; 95% confidence interval, 0.87-1.21; p = 0.79). There was an increase in ischemic stroke as the first event in those on niacin (1.6% vs. 0.9%).

Conclusions:

The authors concluded that among patients with atherosclerotic cardiovascular disease and LDL-C levels of <70 mg/dl, there was no incremental benefit from the addition of niacin to statin therapy during a 36-month follow-up period, despite significant improvements in all lipid parameters.

Perspective:

As with so many other clinical trials in coronary disease that fail to establish the benefit of an additional drug or higher dosing as compared to conventional treatment, AIM-HIGH may have suffered from an unexpected low event rate, the effect of pre-trial statin therapy which reduces plaque instability, inadequate follow-up, the imbalance of statin dosing and addition of ezetamibe favoring the placebo, and the low risk of the study cohort. The increase in ischemic stroke is a concern, but no such signal was seen in a recent meta-analysis. Further, when compared to placebo in the Coronary Drug Project, 3000 mg of niacin was associated with a 26% reduction in ischemic strokes and transient ischemic attacks. This study should not be construed as a failure of strategies to increase HDL-C, but rather intense statin therapy is very effective. The value of adding niacin + laropiprant (prevents niacin flush) to statins will be clarified in HPS2-THRIVE, a clinical trial conducted in 30,000 men and women, in which enrollment is complete.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Aortic Surgery, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Hypertension

Keywords: Cerebral Revascularization, Coronary Artery Disease, Myocardial Infarction, Acute Coronary Syndrome, Follow-Up Studies, Ischemic Attack, Transient, Hypertriglyceridemia, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Peripheral Vascular Diseases, Percutaneous Coronary Intervention, Metabolic Syndrome X, Cholesterol, Dyslipidemias, Cardiovascular Diseases, Cholesterol, HDL, Niacin, Triglycerides, Coronary Artery Bypass, Hypertension, Diabetes Mellitus


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