February 27th, 2013

HPS2-THRIVE Coming Attraction: What Went Wrong with Niacin?

In less than two weeks, on March 9, the main results of the HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events) study will be presented in San Francisco at the annual meeting of the American College of Cardiology. The results have been eagerly awaited since Merck’s brief announcement in December that the trial had not met its primary endpoint and that it would no longer pursue approval of Tredaptive, the combination of extended-release niacin and laropiprant, in the U.S. The trial was designed to assess whether adding the niacin/laropiprant combination to standard statin therapy in high-risk patients would further reduce vascular events.

Now, serving almost as a coming attraction for the main event at the ACC meeting, an important substudy from HPS2-THRIVE has been published in the European Heart JournalThe paper discusses the trial design, the prespecified muscle and liver outcomes, and the reasons for stopping treatment during the trial.

The most important finding in the new paper is that, among the more than 25,000 participants in the study, more than a quarter of patients who were randomized to the niacin arm stopped their treatment, compared with only 16.6% who were randomized to placebo. The most common reasons for stopping treatment were skin-related (chiefly pruritus, rash, or flushing): 5.4% in the combination group versus 1.2% in the placebo group.

Gastrointestinal problems (mostly indigestion and diarrhea) were the second most common cause of treatment cessation: 3.9% versus 1.7%, respectively. Musculoskeletal problems occurred in 1.8% and 1.0%; the risk for myopathy was small but occurred more than four times as often in the combination group, a finding that baffled the investigators, as there is no proposed mechanism by which niacin could cause myopathy. Problems related to diabetes (0.9% vs. 0.4%) were the fourth most common cause of treatment cessation.

The trial investigators reported no difference in liver problems leading to discontinuation of drug treatment, but they did observe that more people in the combination group showed elevated liver-enzyme levels during routine follow-up visits. This increase, found mostly among study participants in China, was largely confined to patients who had muscle damage.

In an accompanying editorial, Ulf Landmesser writes about the failure of niacin within the larger setting of “the difficult search” to find a drug that can work together with statins to further lower vascular events.

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