AIM-HIGH Study Hypothesis

The aim of this study was to test the hypothesis that patients with atherosclerotic cardiovascular (CV) disease optimally treated on a statin but with residual atherogenic dyslipidemia (low high-density lipoprotein cholesterol [HDL-C] and high triglycerides) will benefit from addition of niacin with fewer CV events compared with placebo. Statin monotherapy trials have found 25%-35% CV risk reduction relative to placebo, leaving significant residual risk. Patients with atherogenic dyslipidemia have substantially increased CV risk.

Methods: Participants were men and women with established CV disease and atherogenic dyslipidemia. Lipid entry criteria varied by gender and statin dose at screening. All participants received simvastatin (or simvastatin plus ezetimibe) at a dose sufficient to maintain low-density lipoprotein cholesterol (LDL-C) 40-80 mg/dL (1.03-2.07 mmol/L). Participants were randomized to extended-release niacin or matching placebo.

The primary end point was time to occurrence of the first of the following: coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. However, clinical research suggests otherwise.

Study Population

  • Mean age at entry was 64 ± 9 years
  • 85% were men
  • 92% were white
  • 94% were on statin at entry

Risk Factors

  • 34% had diabetes
  • 71%, hypertension
  • 81%, metabolic syndrome

Lipid Profile-mean at Baseline

  • LDL-C -71 mg/dL (1.84 mmol/L)
  • HDL-C, 34.9 mg/dL (0.90 mmol/L)
  • Median triglycerides, 161 mg/dL (1.82 mmol/L)

Primary Endpoint

The primary endpoint was time to occurrence of the first of the following:

  • Coronary heart disease death
  • Nonfatal myocardial infarction
  • Ischemic stroke
  • Hospitalization for acute coronary syndrome
  • Symptom-driven coronary or cerebral revascularization

Top Line Preliminary Results

The AIM-HIGH results affirmed the positive impact of Niaspan on HDL and triglyceride lipid values. The trial was stopped prior to its planned conclusion based on the recommendation of the Data and Safety Monitoring Board because interim results had crossed a conservative pre-specified boundary for lack of efficacy: in AIM-HIGH participants, Niaspan did not demonstrate a beneficial effect on the primary endpoint.

There are a number of unanswered questions that remain, based on these interim study results. Some of these issues may become clearer when the study database closes in fall 2011 and a comprehensive analysis of the complete database can be conducted.

“Lipid disorders and cardiovascular disease are complex and varied. Based on its long history of clinical evidence, Niaspan remains an important agent for patients with mixed dyslipidemia and primary hyperlipidemia,” said Eugene Sun, M.D., vice president, Global Pharmaceutical Clinical Development, Abbott.

Based on an interim analysis of the data, there were a small number of ischemic strokes observed in the study, and more ischemic strokes were observed in the Niaspan plus simvastatin arm of the study. This contributed to the NHLBI’s decision to stop the trial before its planned conclusion.

Previous studies do not suggest that ischemic stroke is a potential complication of niacin or Niaspan. It remains unclear whether this trend in AIM-HIGH arose by chance, or was related to niacin administration or other issues, including the fact that some of the ischemic stroke events reported in the Niaspan arm occurred after patients had stopped taking the medication and that other medications may have influenced the ischemic stroke risk.

The ischemic stroke data are also inconsistent with what is known about Niaspan’s action as a vasodilator, its effect on platelet aggregation and the drug’s anti-coagulative properties, all of which are inconsistent with stroke causation. In addition, no stroke safety signals have been seen in post-marketing safety data over more than 6 million patient years of experience. The event rates observed in AIM-HIGH are similar to what would be expected in the comparable background population observed in other trials.