Niacin in Patients With Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
Is extended-release niacin added to simvastatin superior to simvastatin alone for reducing the risk of cardiovascular events?
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.
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%).
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.
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.
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, Cholesterol, Dyslipidemias, Cardiovascular Diseases, Cholesterol, HDL, Niacin, Triglycerides, Coronary Artery Bypass, Hypertension, Diabetes Mellitus
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