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Niacin ‘AIM’s-HIGH but Falls Flat

Dec 2, 2011

Niacin boosts HDL cholesterol without benefit for clinical outcomes in otherwise well-treated patients, according to a results of a halted, and perhaps inconclusive, clinical trial.

Extended-release niacin (Niaspan) was associated with a clinical event rate of 16.4% compared with 16.2% in the control group, for a slim 2% relative risk reduction that was not significant at P=0.79 in the AIM-HIGH trial.


William E. Boden, MD, of the State University of New York at Buffalo, and colleagues reported at the American Heart Association meeting and simultaneously online in the New England Journal of Medicine, that the primary trial endpoint encompassed coronary heart disease death, nonfatal myocardial infarction (MI), ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization. None of the individual outcomes differed significantly between groups either.

Boden said at a press conference, “If you are able, as a patient with stable, nonacute cardiac disease, to maintain the levels of [low-density lipoprotein; LDL] control that we did in the study, i.e. in the low 60s, then there is not evidence from this trial to support continued use of niacin for the purpose of reducing further clinical events.”  However, the evidence from this trial is far from a definitive answer on niacin, others warned.

“Whatever conclusions are drawn from this trial, it cannot be emphasized too much that it has not tested the HDL hypothesis, nor was it powered sufficiently to test the potential benefits of niacin,” argued study discussant Philip Barter, MD, of the University of Sydney, who called the trial “appalling.”

The trial was halted earlier this year for futility and a small excess of ischemic strokes in the niacin group, which turned out to be not statistically significant in the final analysis (1.1% versus 1.7%, P=0.11).

But the study may have been doomed from the start because of an overly optimistic 25% effect size expected from niacin, further compounded by the early termination hundreds short of the planned 800 events, Barter noted. Moreover, the study was able to achieve only a 4 mg/dL separation in HDL between treatment groups, though the increase from baseline was greater with niacin as expected (up 25.0% versus 9.8%, P<0.001).

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes trial (AIM-HIGH) randomized 4,414 patients to simvastatin (Zocor, 40 to 80 mg) in combination with high-dose niacin (1,500 to 2,000 mg) or a placebo spiked with 50 mg niacin per tablet to cause flushing to maintain blinding.

Most of the patients were in a secondary prevention population with controlled LDL (under 180 mg/dL) at baseline but low HDL (under 40 mg/dL for men or 50 mg/dL for women). They had already been on a statin for more than a year.

Switching to simvastatin for patients previously on another statin may at least partially have accounted for the HDL boost in the placebo group, Boden suggested.

Because of the active management of LDL, the non-niacin group got more concomitant therapy, noted Steven Nissen, MD, of the Cleveland Clinic, who called the study poorly designed and poorly executed.

Robert P. Giugliano, MD, of Brigham and Women’s Hospital and Harvard in Boston, argued in an editorial accompanying the NEJM article that, despite the negative results, it’s not time to retire the drug. “It would appear to be more prudent to assign it to occasional part-time work, such as in statin-intolerant patients, while we await the results from the much larger Heart Protection Study 2: Treatment of HDL to Reduce the Incidence of Vascular Events trial (HPS2-THRIVE), which is targeted to be completed in 2013,” they wrote.

Practice Pearls:  
  • Explain that niacin boosts high-density lipoprotein (HDL) cholesterol without benefit for clinical outcomes in otherwise well-treated patients.
  • Point out that there was no difference in rates of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization in patients who received niacin compared with placebo.

Boden WE, et al “Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy” N Engl J Med 2011; DOI:10.1056/NEJMoa1107579.