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AIM-HIGH in Dys..

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The Adult Treatment Panel (ATP III) guidelines recommend a primary focus on low-density lipoprotein (LDL) goals as clinical evidence has established a relationship between raised LDL and the risk for coronary heart disease (CHD). It has been suggested that low high-density lipoprotein (HDL), defined as < 40mg/dL, is a good predictor of CHD and is used as a risk factor in determining appropriate LDL goals. High triglycerides (TG), defined as > 200mg/dL, have also been associated with an increased risk of CHD. However, the data is unclear as to how much benefit is achieved by treating low HDL and high TG after optimal LDL goals have been achieved.1,2

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The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides Impact on Global Health Outcomes) investigators conducted a multi-center trial of 3,414 patients with established cardiovascular disease and low HDL/high TG after optimal LDL lowering to evaluate the effect of niacin. Patients were at least 45 years old, with a baseline HDL of < 40mg/dL for men or < 50mg/dL for women, baseline TG of 150-400mg/dL, and baseline LDL of < 180mg/dL if not previously on statin therapy. Eligible patients received simvastatin 40mg daily and either extended-release niacin (Niaspan®), 1500-2000mg daily, or placebo. The LDL goal was 40-80 mg/dL and therapy could be adjusted to achieve LDL goals by adjusting the simvastatin dose or adding ezetimibe 10mg daily. The primary end point of the study was a composite of the first event of CHD death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. Patients were excluded if recently hospitalized for acute coronary syndrome, planned revascularization procedure, or stroke.3,4

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The study was stopped early due to lack efficacy in the niacin group after a three-year period. The primary end point occurred in 16.4% of patients taking niacin and 16.2% of the placebo group (hazard ratio 1.02, with niacin; p=0.80). The rate of ischemic stroke as first event trended more towards the niacin group compared to placebo, 1.6% and 0.9% respectively. Total number of deaths from cardiovascular causes was 45 patients (2.6%) in the niacin group and 38 patients (2.2%) in the placebo group (p=0.47). Niacin therapy resulted in a significant increase of 25% in HDL (42 mg/dL) compared to 9.8% with placebo (38 mg/dL, p<0.001). Discontinuation of niacin was significantly higher compared to the placebo group, 25.4% and 20.1% respectively, however medication adherence was similar.4

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Niacin is commonly used to raise HDL and lower TG after maximally tolerated statin therapy. Despite improvements in HDL and TG, reduced cardiovascular events were not seen with the addition of niacin to patients with cardiovascular disease at LDL goals. Although previous studies have shown benefits with niacin in other outcome measures such as improvements in carotid IMT, this may not translate to clinical benefits.4 The results contradict those from the Coronary Drug Project, where a small reduction of nonfatal MIs with niacin was found 15 years after the trial began.5 Therefore, the duration of the trial may not have been long enough to detect a late benefit with niacin. Also, the authors set the treatment effect to detect a 25% reduction in the primary outcome, which may have been difficult to achieve with the small absolute change in HDL. This trial is not generalizable to some patient populations due to the high number of males and Caucasians and exclusion of patients with recent acute coronary syndromes. Before excluding niacin therapy, further studies are warranted to determine if there could be more benefit with a different niacin formulation (immediate-release niacin) or if certain subgroups of patients could benefit from the addition of niacin. The FDA is currently reviewing the results of the AIM-HIGH trial, to determine if further guidance is warranted regarding the use of extended-release niacin.6 Other trials are ongoing to further investigate the impact of increasing HDL. At this time the focus ...

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