November 15th, 2011

AIM-HIGH: No Benefit for Niacin on Top of Statins

The AIM-HIGH investigators aimed for the lofty target of proving the beneficial effects of niacin therapy. They did not succeed. Their findings were presented Tuesday morning at the AHA  and published simultaneously in the New England Journal of Medicine.

In AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), 3414 patients with CV disease, low HDL, and elevated triglycerides were randomized to either extended-release niacin or placebo in addition to simvastatin. In the niacin group, HDL increased by 25% and triglycerides decreased by 28.6%. In the placebo group, HDL increased by 9.8% and triglycerides decreased by 8.1%.

Follow-up of the trial was stopped early due to futility. The primary endpoint — the first event of the composite of CHD death, nonfatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven coronary or cerebral revascularization — occurred in 16.4% of patients in the niacin group and 16.2% in the placebo group (HR 1.02, CI 0.87-1.21, p=0.79).

More patients in the niacin group than in the placebo group had an ischemic stroke as their first endpoint event (1.6% vs. 0.9%). Although the trend persisted when all ischemic strokes were considered, the investigators note that the overall ischemic stroke rate was low and the imbalance could reflect a “play of chance.” They also observe that similar increases have not been found in previous niacin studies.

Speculating about the lack of niacin’s effect in the trial, the investigators note that the beneficial effects of niacin and gemfibrozil (which also raises HDL) were previously observed in study populations with much higher LDL levels. Aggressive statin therapy, in addition to other contemporary therapies, “may make it difficult to show incremental clinical benefit” from niacin or other new therapies, they write. They add that the true effect of niacin will be definitively assessed in the much larger HPS2-THRIVE study, and that additional studies are underway evaluating other HDL-related therapies.

In an accompanying editorial, Robert Giugliano wonders whether niacin, at 56 years of age, is ready for an early retirement. He writes that the modest difference between the groups of 4-5 mg/dL for HDL would be unlikely to show a large difference in outcomes given the background therapies. He says:

“Given the lack of efficacy shown in this trial, the frequent occurrence of flushing with niacin therapy that some patients find intolerable, and the unresolved question of an increased risk of ischemic stroke, one can hardly justify the continued expenditure of nearly $800 million per year in the United States for branded extended-release niacin.”

Until the final answer about niacin arrives with the HPS2-THRIVE trial, Giugliano endorses a suggestion, proposed in an accompanying perspective by Patricia Maningat and Jan Breslow, that niacin be reserved for statin-intolerant patients.

3 Responses to “AIM-HIGH: No Benefit for Niacin on Top of Statins”

  1. David Kaufman, MD says:

    I still struggle with the results of this study since it seems to contradict so much of what we have learned and proved over the last 50 years. The comment re the editorial gives me pause…and hope. Perhaps the mystery here is that the Niacin seemed to only raise the HDL 4-5 mg/dl. This, of course, is very little, and might explain the failure to prove benefit. The question is: what about in those patients who have a robust response to Niacin with increases in HDL of 35-100%. I have noted over the years the variation in response, ie some with very little and others with amazing increases. Ideally, we should be studying those patients in whom the Niacin “worked”. However, sadly, I now suspect that kind of study will not be done and I fear we may “retire niacin” prematurely.

  2. David Powell , MD, FACC says:

    The investigators could see whether there was an interaction between achieved H DL. and event rate. This would be done with the control arm as well. If the interactions are significant, a claim for special benefit for niacin HDL responders would require comparison with the placebo H DL. responders, as a correlation may exist between H DL. response to niacin and placebo (lifestyle).
    Doubt these comparisons will be statistically sound…may in HPS-2.

    Competing interests pertaining specifically to this post, comment, or both:

  3. I agree with comments by Phil Barter (trial discussant) and Frank Sacks (AHA session panelist). In case you did not hear them, they stated (in very rough paraphrase) that the study was poorly designed and NOT a “game-changer” for niacin use or for the HDL hypothesis.
    Despite the suggestion for an early (actually premature) retirement for niacin in the editorial accomanying the AIM-HIGH publication, the study was never designed to be a test of niacin, and it did NOT succeed in its stated aim as a valid test of the HDL-hypothesis.
    We need to keep in mind several possible reasons for the surprising contrast between AIM-HIGH and prior niacin trials (which had ~7 times MORE total CVD events than AIM-HIGH):
    1. There was no true placebo group.
    a. Control subjects received 200 mg/d of IR niacin (sometimes stated to be 50 mg/d, but actually 50 mg/tablet with 4 tablets/d), which raised their HDL-C by 10% (vs 25% in the full-dose niacin arm) and
    b. More of them took higher doses of simvastatin and
    c. More of them took ezetimibe.
    AIM-HIGH was an active comparator trial! Full-dose vs low-dose niacin plus more aggressive LDL-C lowering (statin + ezetimibe).
    2. The study was stopped early, at a time at which the only other major clinical trial of low HDL-C patients, VA-HIT, was also still negative.
    3. The prior/recent use of niacin in 20% of subjects may have contributed to the neutral result. Remember the “niacin legacy” effect of the Coronary Drug Project.
    NOT helping explain the neutral result:
    1. Despite more aggressive simvastatin and ezetimibe use in the control arm, LDL-C and apo B were still significantly lower than in the full-dose niacin arm. By itself, of course, AIM-HIGH does not disprove the LDL-hypothesis, but it is a notable exception to the rule.
    2. As expected, there was greater TG lowering (and likely there was also greater Lp(a) lowering) in the full-dose niacin arm.
    These two issues further compound (rather than help explain) the mystery of the lack of benefit.
    All that being said, it is possible that the negative AIM-HIGH results might lead to either or both of two surprising conclusions:
    1. Niacin can NOT reduce CVD when added to a statin. Surprisingly, prior to AIM-HIGH there were only a couple of small niacin trials on this question, and they had only a total of 13 CVD events.
    2. Niacin can NOT reduce CVD in patients with low HDL-C. Again surprisingly, prior to AIM-HIGH there were only a couple of small niacin trials on this question, and they had only a total of 38 CVD events.
    If either of the above are proven to be true, those of us who use a lot of niacin will need to cut WAY back on its use! Unfortunately, AIM-HIGH likely cannot be a clear test of either possiblity (except perhaps in part if there is a strong inverse relationship between duration of prior statin use and CVD benefit in post-hoc analyses).
    Fortunately, solid evidence regarding these two possibilities and resolution of the various weaknesses and conundrums of AIM-HIGH (above) will very likely come from HPS2-THRIVE, which has 7 times more subjects, a true “placebo” arm, a broad range of baseline HDL-C, and much less prior statin (or niacin) use. HPS2-THRIVE results should be available in about 12 months, so I agree with Frank Sacks that we should not be in a big rush to throw out 57 years of niacin trials on the basis of the modest-sized and convoluted AIM-HIGH study.

    Note: although I freely declare my many conflicts, I invite the reader to judge the above arguments on their scientific merits (or demerits), rather than on the knee-jerk “all-pharma-conflicted-individuals-are-always-biased-in-favor-of-pharma” model, which is prevalent as a politically-correct dogma in medicine today.

    Competing interests pertaining specifically to this post, comment, or both:
    Research grants and speaking and consulting honoraria from Abbott and Merck (manufacturers of branded niacin) and honoraria from other companies which make statins and other competitors for niacin.