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December 20th, 2012

HPS2-THRIVE: No Benefit, Signal of Harm for Niacin Therapy

The largest-ever study of niacin has failed to show a clinical benefit of niacin and even found a strong signal of harm. Merck announced today that the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study did not meet its primary endpoint. In that study, the combination of a statin and Merck’s niacin compound, Tredaptive, a combination of extended-release niacin and laropiprant, an anti-flushing agent, was compared with statin therapy alone in 25,673 patients at high risk for cardiovascular events.

After a median follow-up of 3.9 years, the combination of niacin and laropiprant “did not significantly further reduce the risk of the combination of coronary deaths, non-fatal heart attacks, strokes or revascularizations compared to statin therapy,” according to Merck. Even more troubling, the company reported that there was “a statistically significant increase in the incidence of some types of non-fatal serious adverse events in the group that received extended-release niacin/laropiprant.”

Merck said it is no longer planning to seek FDA approval of Tredaptive in the United States. The drug’s initial application for approval in the U.S. was rejected in 2008. HPS2-THRIVE was designed to answer criticism from the FDA and other experts about the lack of evidence demonstrating clinical benefit.

Tredaptive (also known as Cordaptive in some places) is approved in some countries outside the U.S. Merck said it is “recommending that providers not start new patients” on the drug. It is unclear whether the drug will remain on the market in these places.

Although niacin, a natural vitamin, has been used for decades to raise HDL, a clinical benefit has never been demonstrated. In 2011 the NIH’s  AIM-HIGH trial found no benefit for extended-release niacin. Critics said the trial was underpowered and otherwise flawed. HPS2-THRIVE, most agreed, would provide a more definitive test of the effect of niacin.

HPS2-THRIVE adds to a string of failures associated with trials of HDL-related therapies, although some hope remains for CETP inhibitors, despite the failure of two large clinical trials. It appears likely that the results of HPS2-THRIVE will also affect the use of existing niacin products. Bernstein analyst Timothy Anderson said it may “cause some collateral damage to AbbVie’s Niaspan.”

Responding to the breaking news, Steve Nissen said he had three initial thoughts about the trial:

What were the “non-fatal serious adverse events” that showed a statistically significant increase?

Did the study fail because of niacin or laropiprant?

We will need to decide whether to withdraw patients from niacin.

Categories: Prevention
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2 Responses to “HPS2-THRIVE: No Benefit, Signal of Harm for Niacin Therapy”

  1. William L Blanchet, MD says:
    December 22, 2012 at 11:19 am

    Lessons in how to misinterpret DATA.

    It is highly probable that laropiprant has a negative effect on vascular health that negates the benefit of niacin. This headline damming niacin is a great example of poor science and a grave disservice to those suffering from vascular disease. If we did a study of lipitor plus vioxx to mitigate the muscle soreness from the lipitor, would we conclude that lipitor was of no value?

    See: J Am Coll Cardiol. 2012;():. doi:10.1016/j.jacc.2012.10.030 where niacin was shown to be of significant benefit in CVD.

  2. Joel Wolkowicz, MDCM says:
    December 22, 2012 at 7:09 pm

    Very interesting. And Dr. Blanchet’s evidence that niacin saves lives is what?