Niaspan and how comparative effectiveness research was done well

Comparative effectiveness research — investigations that determine which treatments are best — has attracted attention in the health care debate. Critics charge that these studies are designed to restrict choice. The Center for Medicine in the Public Interest released a report that suggested that they would stifle innovation. Often they are framed as studies to support efforts to keep useful but expensive therapies from patients.

But what if these studies, done well, revealed that some medications were better than others? What if they overturned conventional wisdom about understudied drugs, demonstrating that many patients were receiving ineffective treatments? What if they showed that some patient were actually being harmed? What if more knowledge about the benefit and risk of treatments in medicine, compared with their alternatives, is just what patients need?

Recently, we had an example of comparative effectiveness research done well. The National Institutes of Health (NIH) has produced a gem of a study with critical implications for patient decisions and lessons for future research. The study, called AIM-HIGH, was designed to evaluate whether adding Niaspan, a proprietary formulation of extended release niacin sold by Abbott Laboratories (Abbott Park, IL), to statin treatment in patients with heart and vascular disease would reduce their risk.

Niacin, also known as nicotinic acid or vitamin B3, is one of the body’s essential nutrients. In high doses niacin increases the good cholesterol (HDL) and decreases triglycerides. The drug causes several unpleasant side effects that limits its use in high dose, including an uncomfortable flushing sensation. The extended release niacin is better tolerated and often prescribed to patients. Whether the drug reduces a person’s risk of heart disease is not known.

The AIM-HIGH investigators enrolled 3,414 patients who had cardiovascular disease and were taking statin drugs to reduce their risk. These patients had low levels of the HDL cholesterol and high levels of triglycerides, markers of increased risk. The subjects were randomly assigned to Niaspan or placebo and observed for several years.

Although the study has yet to be published, enough information was released last week to give us a good picture of the results. The trial was stopped more than a year early because there was not a hint of benefit for patients to this point, making further evaluation unnecessary. There was even a suggestion of harm, with more strokes in the Niaspan group – but that may have been a chance occurrence.

The NIH study is an example of comparative effectiveness research that can be embraced by patients, clinicians, industry, payers and government because of their approach. Let’s take a close look at what they did right.

1. The study targeted an important area of uncertainty for patients. Niaspan is a popular drug that is known to raise the HDL cholesterol and decrease triglycerides. Sales of the drug last year were close to $1 billion. Unfortunately we do not know whether the drug reduces the risk of heart disease or stroke – or improves survival.

The approval of the drug was based on its effect on laboratory tests, not patient outcomes. This proprietary formulation that is touted widely in direct-to-consumer advertising and in colorful promotional pages in medical journals is not known to reduce patient risk when added to a statin drug. We have evidence from other studies that drugs that modify risk factors do not always affect patient risk in predictable ways. The only large study of niacin (not the extended release formulation) was conducted more than 30 years ago, before treatment with statins and the current era heart care.

Patients could make better decisions about whether to take this medication by knowing if it reduces their risk when added to a statin drug.

2. The study compared Niaspan with the a reasonable alternative strategy. Too often studies compare one drug with an inferior strategy. In this case, Niaspan was compared with good treatment with a statin and sometimes another drug to ensure that the bad cholesterol (LDL) was properly controlled. Statins are known to reduce risk and would be considered standard care for these high risk patients.

It was essential that Niaspan be tested in conditions that replicate the scenario in which patient need to decide with their clinicians about adding another medication. The study appropriately asks whether it is useful to add Niaspan to the regimen of patients who are taking statins.

3. The conclusions of the study did not go beyond the evidence. The press release focused on the absence of an effect of Niaspan, but did not generalize further to other drugs that may affect the levels of HDL cholesterol. Each drug must be tested in its own right because it has its own spectrum of effects on human biology and it is likely that there are many effects for each drug that are yet to be uncovered. Even within a class we have seen marked differences in the risk profiles of drugs – with Baycol and Zocor as examples – or Avandia and Actos.

Also, the investigators noted that the results should not be extrapolated to other patient populations. Whether there are specific groups who might benefit is unknown. What this study can say is that the only large study of this drug in a relatively high risk population has failed to detect an important benefit.

4. The NIH and Abbott were involved in the study. The NIH and the study investigators were wise to involve Abbot because it relieved taxpayers from paying the entire bill and engaged the company in a test of its product. Abbott Laboratories paid more than half of the $52 million study costs. Their involvement demonstrates a degree of consent to the study and commitment to it. Abbott should be commended for supporting the study and seeking truth about the effect of their drug on patient outcomes. No pharmaceutical company should want to sell a product that does not help patients. Abbott demonstrated their values by supporting a test of a billion dollar drug whose sales were based on an assumption of benefit. Moreover, Abbott did not criticize the study.

Having NIH oversee the study was also important. The NIH has impeccable research credentials and their policies and procedures protect the scientific integrity and transparency of the process. Unfortunately many industry trials have been tainted by concerns of misbehavior in the handling of data and the publication process. The credibility of this study was assured by its conduct under the auspices of the NIH.

5. The study had close oversight by an independent advisory group. The study had an independent group of experts protecting the interests of the patients. These experts were looking at the results as they were accumulating and entrusted with decisions about whether it was worthwhile to continue the study. They were also monitoring for any dangerous effects of the drugs that would mandate stopping the trial. They were the only ones who were allowed to see the results as the study progressed. It was their decision to stop the study based on the statistical certainty that it would not show Niaspan to be useful. Having such an independent group, which is not controlled by the sponsors and is accountable to the subjects, is essential in these studies.

The challenge is now to act on the information. The information that was released should be considered reliable enough to inform patients that adding Niaspan to statin treatment does not reduce patient risk even as it does change HDL cholesterol and triglyceride levels. Every patient on this drug – every patient for whom this drug is contemplated – should receive the information that was presented by the NIH and its investigators about AIM-HIGH.

We will learn more when the study is formally presented. The scientists need some time to perform all the analyses that were specified in their protocol. But the major finding is now known and dissemination of the information to patients should occur.

This is the type of comparative effectiveness study that we need. The focus is on describing how one strategy compares with another with respect to risks and benefits that patients experience. Patients are better informed about Niaspan than they were a week ago. The better information will presumably lead to better decisions. It is an outcome we should all embrace … and seek.

Harlan M. Krumholz is a professor of cardiology, epidemiology and public health at Yale University School of Medicine. He blogs at Forbes, where this article originally appeared.

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  • Frank in L.A.

    I am not familiar with the “Center for Medicine in the Public Interest.” But, if someone formed an organization with a name so similar to the “Center for Science in the Public Interest,” one would immediately wonder if the two organizations are connected (informally or otherwise)?

    The “Center for Science in the Public Interest” has a long history of promoting scientifically questionable agendas, so the alarm bells immediately go off when hearing the similar name “Center for Medicine in the Public Interest.”

    Can Dr. Krumholz provide any evidence that the “Center for Medicine in the Public Interest” is the type of organization that we can rely on for legitimate, unbiased information? I would also ask Dr. Krumholz to disclose whether he has any connection to the “Center for Medicine in the Public Interest.”

  • Harlan Krumholz

    Honestly, I don’t know anything about them. I used their report, which received some coverage, as an example of those who are suggesting that comparative effectiveness research will harm medicine. If you read my blog you will see that I do not agree with that view.

  • http://www.BocaConciergeDoc.com Steven Reznick MD

    There has been much leaked out about this study before publication. My pet peeve is about information leaked out and broadcast through the media before the general scientific community has an opportunity to review it , discuss it , dissect it and reflect upon it. This study was not stopped early because people became ill and died from the treatment. The paper deserves to go through the scientific process BEFORE press conferences and suggestions to patients.

    I believe no mention was made of the role of niaspan in lowering triglycerides to prevent pancreatitis? I think the media has to be very specific about what the study indicated after the study has an opportunity to be reviewed and discussed. His article in Forbes magazine was premature in my opinion because it bypassed the discussion and reflection period and went straight to the lay public.

    • Leo Holm MD

      The DTC commercials for Niaspan also bypassed the scientific community and went straight to the public to suggest therapy to them. I had to see a lot of those annoying and misleading commercials until science decided to intervene. I wonder how much money they made during that time? Indeed, the media should be more careful.

  • Moshe

    One issue I have with the study is that it is only relevant for those with prior CV disease.

    Does Niacin work to prevent CV disease as primary prevention in young adults with very low HDL? I don’t know for sure, but the current AIL-HIGH study does not give us any information to decide such a question.

  • Harlan Krumholz

    This was not information that was leaked out – the information here was formally presented by the investigators and the NIH – based on the assessment of an independent panel of experts. The study was ended early and the rates of the primary endpoint were presented. I stated in my piece that there will be more to learn – but the likelihood that the final paper will state that Niaspan is superior to placebo is practically nil. And what I was arguing was that patients should know. This $1.6 billion drug is not primarily being prescribed to prevent pancreatitis – or but to reduce cardiovascular risk. There was little evidence of its benefit when added to statins before AIM-HIGH – and less now – and waiting to tell patients seems to deny them the chance to decide for themselves if they want to take the medication. It would certainly be fair to tell them also that the main publication has yet to be released. But this was not a leak. It was a prepared presentation about a study that was stopped early – and NIH released the information because it was confident in it and felt it was in the public interest. I agree.

    To Moshe: Yes, this is for high risk patients… but not sure why it would be more effective in lower risk populations. In any case, no evidence yet that it is. And the benefit in lower risk populations is harder to show.

    • http://www.BocaConciergeDoc.com Steven Reznick MD

      Traditionally the results of the study would have been released by a publication in a journal. In the last 15 years it has become customary ( not necessarily ethical or a positive for the profession) to hold a press conference the day the article went into print. This assured that the media broadcast the results of the study and conclusions before anyone in the scientific community had an opportunity to receive the journal and read the study, ask questions and critique it. Important material was usually discussed at professional meetings. This usually led to further studies.
      Today the Wall Street Journal is running an article about a topic and a blog is out there on it before anyone in the health care or scientific community gets a chance to see it. This is a ” leak” regardless of how you wish to present it. The leak is done by some for financial gain. The leak is done by others for personal ego and by others because they think their conclusion is of such public health importance that it supersedes a review and discussion process. The same academic journals that feel free to take advertising from pharmaceutical houses and others for profit and sustenance are quick to criticize community based physicians ( ” those LMD’s” as they are referred to disparagingly on teaching rounds) for finding a way to stay economically viable and keep current.
      Your piece is well written . The participation of the NIH and the pharmaceutical house give the study validity. I still believe it is premature to be offering advice without an opportunity for the scientific community to read the study first. This is a leak.

  • Moshe

    Dr. Krumholz,

    The study was run for about 3 years. The development of arterial plaques takes tens of years. The fact that HDL does not reverse the damage is not indicative of it not preventing the damage as it occurs.

    Statins, on the other hand, also help prevent additional damage – possibly by stabilising the fibrous cap of the plaque.

  • Harlan Krumholz

    Thanks for sharing your views. Certainly agree that there is a tension between rapidly sharing new information with the public and profession – and holding off for a paper to be published and discussed. And with regard to LMDs – without physicians in practice throughout the country where would we be. Our goal should be to work together for the common good. And having these types of conversations where disparate views are share should be welcomed on all sides.

  • Harlan Krumholz

    Moshe: It is a reasonable idea. The sample size for a primary prevention cohort will need to be quite large. I wonder if it will ever be done. For now, we just don’t know.

  • Michael Halpern

    I’m a patient, not an MD. Not mentioned was niacin’s ability to lower my Lp(a), which I understand is atherogenic. Further, there is a low-cost generic equivalent to Niaspan (at least as far as reducing unpleasant flushing) called Slo-Niacin. Until I switched away from Niaspan this drug cost a lot more than my Crestor. .