The AIM-HIGH trial: residual macrovascular risk not reduced by extended-release niacin but was the objective too ambitious?

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1 November 2011

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) showed no clinical benefits of extended-release niacin given on top of high-dose simvastatin in patients with cardiovascular disease and atherogenic dyslipidemia. This apparent lack of efficacy led to a premature termination of the trial.

AIM-HIGH Investigators

STUDY SUMMARY

Objectives

To test whether tested whether extended-release niacin added to intensive statin therapy, as compared with statin therapy alone, would reduce the risk of cardiovascular events in patients with established atherosclerotic cardiovascular disease and atherogenic dyslipidemia.

Inclusion criteria

Patients aged 45 years or more with established atherosclerotic cardiovascular disease (documented stable coronary heart disease, cerebrovascular or carotid disease, or peripheral arterial disease) and:

LDL-C <180 mg/dL (4.65 mmol/L) or receiving statin therapy at study entry
HDL-C <40 mg/dL (1.03 mmol/L) for men; <50 mg/dL (1.29 mmol/L) for women
Triglycerides = 150 to 400 mg/dL (1.69 to 4.52 mmol/L)

Interventions

All patients were treated with simvastatin 40 to 80 mg per day, plus ezetimibe, 10 mg per day, if needed, to maintain an LDL-C level of 40 to 80 mg/dL (1.03 to 2.07 mmol/L)
On top of simvastatin, patients were randomly assigned to:

Extended-release niacin 1500 to 2000 mg per day
Matching placebo

Primary endpoint

Composite of death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization

Main results

3,414 randomized patients (male sex, 85%; mean age, 63.7 years)
Lipid changes at 2 years: summarized in Table 1.
No significant difference (niacin vs. placebo) in primary endpoint in a pre-planned interim analysis after a mean follow-up of 36 months:
Hazard ratio, 1.02; 95% confidence interval, 0.87-1.21; P=0.79
Apparent, but not significant increase in ischemic stroke incidence in the niacin group: HR, 1.61; 95%CI, 0.89-2.90; p=0.11

Table 1. Median lipid changes from baseline at 2 years*
	Niacin group	Placebo group
HDL-C†	+25% (from 35 to 42 mg/dL)	+9.8% (from 35 to 38 mg/dL)
Triglycerides	–28.6% (from 164 to122 mg/dL)	–8.1% (from 162 to 153 mg/dL)
LDL-C	–12.0% (from 74 to 62 mg/dL)	–5.5% (from 74 to 68 mg/dL)

COMMENT

AIM-HIGH was clearly designed to see whether intervening on atherogenic dyslipidemia with extended-release niacin would reduce the residual risk of major macrovascular events in patients treated with a high-dose statin. The trial was initially designed for a mean follow-up of 4.6 years but was prematurely stopped after 3 years because of an apparent lack of efficacy of extended-release niacin.

There were solid reasons to evaluate the efficacy of extended-release niacin in this indication. Niacin (nicotinic acid) is known to act on the two main components of atherogenic dyslipidemia, increasing HDL cholesterol levels by 20-25% and decreasing triglyceride levels by 20-30%. In the Coronary Drug Project,1 a trial conducted before the statin era, immediate-release niacin significantly decreased the rate of cardiovascular events in patients with established CVD. A reduction of cardiovascular events was also seen in patients treated with simvastatin + niacin in the HDL-Atherosclerosis Treatment Study (HATS).2 In the ARBITER 6-HALTS study,3 slow-release niacin added to background statin therapy was more effective than ezetimibe in reducing carotid intima-media thickness. A meta-analysis of 11 randomized controlled clinical trials found positive effects of niacin alone or in combination on all cardiovascular events (coronary events and strokes) and on atherosclerosis evolution.4

With such a promising background, the premature termination of the AIM-HIGH study for lack of efficacy was unexpected, all the more so as changes in lipid levels in the extended-release niacin group were in line with those reported in previous trials.

Early termination of a trial, especially on “futility” grounds rather than safety or tolerability issues, often generates criticism. Some of the experts present at the November 2011 AHA meeting – where results of AIM-HIGH were first released publicly declared that no firm conclusion could be drawn from the trial. AIM-HIGH was stopped for futility, meaning that the investigators had decided to stop it early if a pre-planned interim analysis suggested a small probability of success of the intervention tested. Futility analyses have an economic objective: early termination of trials that will probably have negative results might reduce unnecessary research spending. However, the greatest disadvantage of a futility-stopping rule is that it makes difficult to draw useful conclusions from a negative study.5

The study was designed to have 85% power to detect a 25% reduction in the primary endpoint, which was also criticized on retrospect as overambitious, given the fact that many a recent trial were characterized by lower-than-expected cardiovascular events rate.

In contrast with previously reported data, in particular from the meta-analysis quoted above,4 the number of ischemic strokes was surprisingly higher in the extended-release niacin group than in the placebo group. A careful review provided no evidence of a causal link, the authors write. This unexpected finding might have been due to the statistical “play of chance.”

Discussing with Dr. Robert Rosenson (New York, NY, USA)*, Dr. Philip Barter (Sydney, Australia) and Dr. Bryan Brewer (Washington, DC, USA) said they would wait the results of the ongoing Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial to have a firm opinion about the role of extended-release niacin in cardiovascular prevention.

HPS2-THRIVE, a multinational randomized clinical trial with a much larger recruitment than AIM-HIGH (20,000 participants with vascular disease included) investigates the efficacy of extended-release niacin in patients with LDL cholesterol optimized with statin-based therapy. In this trial, patients in the niacin group also receive a specific blocker of prostaglandin D2 to limit flushing, the major side-effect of niacin. HPS2-THRIVE is one of the next major trials exploring HDL-targeted therapies for the reduction of macrovascular residual risk.

*Dr. Rosenson is member of the International Steering Committee of the R3i.

References

The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA1975;231:360-81.
Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med 2009;361:2113–22.
Bruckert E, Labreuche J, Amarenco P. Meta-analysis of the effect of nicotinic acid alone or in combination on cardiovascular events and atherosclerosis. Atherosclerosis 2010;210:353–61.
Meade MO. Pro/con clinical debate: It is acceptable to stop large multicentre randomized controlled trials at interim analysis for futility. Con: the hazards of stopping for futility. Crit Care 2005;9:34-6.