Is niacin ineffective? Or did AIM-HIGH miss its target?

AIM-HIGH end points

The primary end point was the composite of the first event of death due to coronary heart disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven revascularization of the coronary or cerebral arteries.

Secondary end points were:

• Death from coronary heart disease, nonfatal myocardial infarction, ischemic stroke, or hospitalization for acute coronary syndrome
• Death from coronary heart disease, nonfatal myocardial infarction, or ischemic stroke
• Death from cardiovascular causes.

Tertiary end points included:

• Death from any cause
• Individual components of the primary end point
• Prespecified subgroups according to sex, history or no history of diabetes, and presence or absence of the metabolic syndrome.¹

All clinical events were adjudicated by a central committee.

STUDY HALTED EARLY

The study was planned to run for a mean of 4.6 years, during which 800 primary end point events were expected. With these numbers, the investigators calculated that the study had 85% power to detect a 25% reduction in the primary end point, at a one-sided alpha level of 0.025.

The plan called for an interim analysis when 50% of the anticipated events had occurred, with prespecified stopping boundaries based on either efficacy or futility. The boundary for lack of efficacy required an observed hazard ratio of at least 1.02 with a probability of less than .001.

In the interim analysis, after a median follow-up of only 3 years, the data and safety monitoring board recommended stopping the study early because the boundary for futility had been crossed and, unexpectedly, the rate of ischemic stroke was higher in the niacin-treated patients than in those receiving placebo.

MAJOR FINDINGS OF AIM-HIGH

Of 4,273 patients who began open-label treatment with niacin, 3,414 were randomized to treatment with niacin or placebo.¹

HDL-C levels went up in both groups

At 2 years:

• HDL-C levels had increased by 25.0% (to 42 mg/dL) in the niacin group and by 9.8% (to 38 mg/dL) in the placebo group
• Triglycerides had decreased by 28.6% with niacin and by 8.1% with placebo
• LDL-C had decreased by 12.0% with niacin and by 5.5% with placebo.

Patients in the placebo group were more likely to have subsequently received the maximum dose of simvastatin, ie, 80 mg/day (24.7% vs 17.5%), and to have received ezetimibe (21.5% vs 9.5%). More patients in the niacin group required either dose reduction of the study drug (6.3% vs 3.4%) or drug discontinuation (25.4% vs 20.1%).¹

No difference in the primary end point

There was no difference between the two treatment groups in the rate of the primary end point, which occurred in 282 (16.4%) of the 1,718 patients in the niacin group and 272 (16.2%) of the 1,696 patients in the placebo group (P = .79; hazard ratio 1.02, 95% confidence interval 0.87–1.21).¹

However, more patients in the niacin group than in the placebo group who reached the primary end point did so by having a first ischemic stroke: 27 patients (1.6%) vs 15 patients (0.9%). Eight of these patients, all in the niacin group, had their stroke between 2 months and 4 years after they had stopped taking the study drug.

Further analysis that included all ischemic strokes revealed the same trend: 29 vs 18 patients (P = .11).¹

No benefit was observed for niacin-treated patients in terms of any of the secondary or tertiary end points.

Subgroup analysis revealed no evidence of statistical heterogeneity: ie, niacin seemed to lack efficacy in all the prespecified subgroups studied (age 65 and older vs younger, men vs women, and those with or without diabetes, metabolic syndrome, prior myocardial infarction, or statin use at entry).

In general, niacin was well tolerated in the active-treatment group, with a low incidence of liver and muscle abnormalities.

PUTTING AIM-HIGH IN CONTEXT

How should practicing clinicians interpret these outcomes?

Ever since the NHLBI reported (in an urgent press release) that it was stopping the study early due to futility and a potential excess of strokes,¹³ there has been considerable debate as to which factors contributed to these outcomes. In the wake of the publication of more detailed information about the trial,¹ this debate is likely to continue.

The AIM-HIGH results can be interpreted in several ways:

• Perhaps niacin is no good as a preventive agent
• Perhaps raising HDL-C is flawed as a preventive strategy
• Perhaps AIM-HIGH had methodologic flaws, such as looking at the wrong patient cohort or using a treatment protocol that set itself up for failure
• Perhaps statins are so good that, once you prescribe one, anything else you give provides no additional benefit.

Which of these is correct?

Is niacin no good?

In its most simple form, AIM-HIGH has always been seen as a clinical trial of niacin. While the early trials of immediate-release niacin were encouraging in terms of its effects on lipids, atherosclerotic plaque, and cardiovascular outcomes, using it in clinical practice has always been challenging, largely because many patients cannot tolerate it in doses high enough to be effective. A number of developments have improved niacin’s tolerability, but its clinical impact in the statin era has not been evaluated.

Niacin’s lack of efficacy in this trial will ultimately be viewed as a failure of the drug itself, but is this the case?

AIM-HIGH was not simply a direct comparison of niacin vs placebo on top of standard medical practice. The investigators recognized that niacin has additional effects—in particular, lowering levels of atherogenic lipids—and they attempted to control for these effects by titrating the other LDL-C-lowering therapies during the study. As a result, the trial was actually a comparison between niacin plus low-dose simvastatin on the one hand, and placebo plus high-dose simvastatin (and, more often, also ezetimibe) on the other.

Furthermore, the placebo-treated patients received small doses of immediate-release niacin to induce flushing and maintain blinding. It is therefore hard to conclude that this clinical trial was a direct evaluation of the impact of niacin.

In contrast, the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) study is currently evaluating extended-release niacin in combination with laropiprant, a prostaglandin receptor antagonist, vs placebo in more than 24,000 statin-treated patients.¹⁴ Without any in-trial titration of lipids, this study provides a more direct comparison of the effects of niacin in the statin era.

Niacin continues to attract interest, largely because it can raise HDL-C by 20% to 30% when given at doses of 1,500 mg or more. Also, consistent observations from population studies of an inverse relationship between HDL-C levels and cardiovascular risk⁵ have stimulated interest in developing novel agents that substantially raise HDL-C.