May 26th, 2011

NHLBI Stops the AIM-HIGH Trial of Niacin

The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) trial of niacin has been stopped early by the NHLBI. The trial was designed to test the addition of high-dose, extended-release niacin to statins in people at risk for CV events who had well-controlled LDL but low HDL and elevated triglyceride levels.

The trial was stopped early after a regularly scheduled meeting on April 25, 2011 of the data and safety monitoring board (DSMB) determined that there was no difference in the rate of clinical events between the two treatment groups. As expected, niacin was effective at raising HDL and lowering triglyceride levels, but it had no effect on the composite endpoint of fatal or nonfatal MI, strokes, hospitalizations for ACS, or the rate of revascularization procedures.

At an NIH press conference, the study director, Ruth McBride, reported that the annualized rate of the primary endpoint was 5.6% in the control group and 5.8% in the niacin group. In addition, there was a small and unexplained increase in the rate of ischemic strokes in the niacin arm. During the 32-month followup period, there were 28 strokes (1.6 %) in the niacin group versus 12 strokes (0.7%) in the control group. An NIH/NIHLBI press release noted that 9 of the 28 strokes in the niacin group “occurred in participants who had discontinued the drug at least two months and up to four years before their stroke” and that previous research has not raised a warning flag about an elevated risk of stroke associated with niacin use.

Starting in 2005, 3,414 patients were enrolled in AIM-HIGH, which was funded by the NHLBI with additional support from Abbott, which also supplied the niacin formulation (Niaspan) used in the study. The NHLBI noted in its press release that several previous trials, including the ACCORD trial with fenofibrate and the ILLUMINATE trial with torcetrapib, have failed to demonstrate the beneficial effects of HDL-raising drugs.

“This study sought to confirm earlier and smaller studies.,” said Susan B. Shurin, the acting director of the NHLBI, in the press release. “Although we did not see the expected clinical benefit, we have answered an important scientific question about treatment for cardiovascular disease.”

“The results from AIM-HIGH should not be extrapolated to apply to potentially higher-risk patients such as those with acute heart attack or acute coronary syndromes, or in patients whose LDL cholesterol is not as well-controlled as those in AIM-HIGH,” said William Boden, M.D, the co-principal investigator of the study.

At the NIH press conference, Boden said he would consider using niacin in an ACS patient with an LDL level of 140 and an HDL level of 25. He expressed concern that “there will be a temptation to interpret this trial as a quote unquote negative trial.”

In a statement, the FDA said it had “made no new conclusions or recommendations regarding the use of extended-release niacin alone or in combination with simvastatin or other statins” and said it would “conduct a comprehensive review of the AIM-HIGH trial data as soon as they become available to determine their impact on the approved indications for extended-release niacin.”

We appreciate all of your great comments about AIM-HIGH both below and at our Voices blog, “AIM-HIGH Halted: Death Knell for for the HDL Hypothesis? Six Experts Weigh In.” To keep the discussion moving — but in one place — we’re closing out the thread below and hope that you will continue talking here.

10 Responses to “NHLBI Stops the AIM-HIGH Trial of Niacin”

  1. Bill Boden’s comment reflects the fact that “this dog won’t die easy.”

  2. It is a great tragedy that this study was discontinued early. To predict no outcomes before clinical significance is reached is just scientifically and mathematically wrong! It is also wrong that the composite endpoint was used rather than MI or coronary death and all cause mortality being used. In addition, if someone discontinues a treatment, the adverse event associated with that subject should not be counted in the treatment group.

    The NIH has wasted my tax money and wasted a potentially great study by terminating it early.

    Truth survives and likely in the future when we better understand the role of nicotinic acid in coronary prevention, this decision will be viewed as an insanely bad decision.

    Competing interests pertaining specifically to this post, comment, or both:
    I use nicotinic acid routinely in coronary prevention in my practice. The incidence of events in my elderly Internal Medicine practice over the past 6 years is 0.01%. Nicotinic acid provides a significant contribution to that success.

  3. Brian Scanlan, MD says:

    Will this decision affect in any way the TV direct marketing of Abbott’s product? The current ad campaign implies that Niaspan is the only thing between life and death for many persons with coronary artery disease.

    Competing interests pertaining specifically to this post, comment, or both:
    I receive no compensation from TV networks or pharmaceutical firms.

  4. Micah Eimer, MD says:

    This confirms what we saw in Jupiter about the role of HDL in the setting of low LDL. Not sure if the stroke signal is noise or not but with nothing to be gained on Niacin in these patients why take the risk?

    Glad they used hard end points. Hopefully they have some data on particle size so we can stop talking about that too.

  5. This study again reinforces that the larger picture ( composite end point or the whole of Lipid profile) is more important than playing with a single Risk factor.

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

  6. Let me try to address Dr. Blanchet’s concerns regarding the AIM-HIGH trial.

    Consistent with good clinical trial practice, AIM-HIGH had a prespecified stopping rule. Such rules are typically enacted after interim analyses yield unacceptable safety, futility, or large treatment effect. The AIM-HIGH was stopped for futility. In the expert opinion of the DMSB, the probability of finding a “clinically important” and “statistically significant” treatment effect was highly unlikely.

    The choice of composite endpoint in AIM-HIGH was driven by, amongst other things, considerations of trial efficiency and feasibility. Focusing on death or MI as a primary endpoint would have inflated the sample size and rendered the trial difficult to conduct.

    The intention-to-treat principle is critical to maintaining the advantages of randomization and is the “gold standard” for assessment of efficacy outcomes (ischemic stroke was a part of the primary efficacy endpoint in AIM-HIGH).

    I do not see clinical trials, either those that are stopped early or those that yield null results, as a waste of effort and resources. There are always important lessons to be learnt. Hopefully, AIM-HIGH will also teach us important lessons when all the results are released. One question that we might want to reconsider is whether ‘residual risk’ in patients that are optimally treated with statins can be modified or not. Another question we need to ponder is whether lipid-modifying therapies should be approved on the basis of improved lipid biomarkers (the current regulatory standard) or improved hard outcomes.

  7. There are previous studies in the literature that show benefits of Niacin. The 15 yr follow up of the Coronary Drug Project showed an improvement in all cause mortality at 15 years (but not in the original 5 year study.) Arbiter 6 halts showed improvement in Carotid IMT compared to ezetamibe. Coronary Drug Project used crystalline niacin while the Arbiter 6 used Niaspan.

    I believe that the early termination of Aim High raises multiple questions.
    1. Are potent statins like 40 mg of simvastatin so strong in their effects that no other lipid lowering treatments (niacin, fibric acid drugs, ezetamibe, etc) are necessary for proper care of patients?
    2. Are crystalline preparations of Niacin superior to extended release products?
    3. Are biomarkers such as carotid IMT “over calling” disease that won’t cause events in the future?
    4. Will niacin show a late effect as it did in the coronary drug project.

    I don’t believe we have answers to these questions as yet and look forward to reading the full publication of AIM High data.
    As of now, I read these results as Statins first, statins early and statins in appropriate doses. All other treatments are distant secondary additions.

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

  8. Thomas Barringer, MD says:

    Non-HDL-C values were just over 100 in both treatment arms, which suggests that the apo B (or LDL-P) values were also not significantly different. Therefore, this trial result supports the concept that atherogenic particle number is the critical factor in determining clinical outcome. As long as the apo B (or LDL-P) is the same, whether achieved with a statin alone, a statin plus ezetimibe, or a statin plus niacin, the clinical outcome is the same. Further confirmation of this principal, already demonstrated in studies comparing drugs of the same class (ie statin vs statin), and now shown in a short-term study using drugs from different classes, is a valuable contribution.

    Competing interests pertaining specifically to this post, comment, or both:
    speakers bureau for Abbott and GSK

  9. Lots of interesting comments. This study certainly adds more concern about a reliance on surrogates in directing clinical decisions. I did like many aspects of this trial and look forward to reading the report. In the meantime, Niaspan has no evidence that when added to statin therapy that it reduces risk.

  10. We appreciate all of your great comments about AIM-HIGH — both here and at our Voices blog, “AIM-HIGH Halted: Death Knell for for the HDL Hypothesis? Six Experts Weigh In.” To keep the discussion moving — but in one place — we’re closing out the above thread and hope that you will continue talking here.