SAN FRANCISCO, CA—The role of extended-release niacin for the treatment and prevention of cardiovascular disease needs to be reconsidered in light of the “significant excesses of serious adverse events (SAEs) of both known and unrecognized side effects of niacin,” concluded the Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), the largest randomized trial to date to assess the agent’s clinical efficacy and safety, at ACC.13, the American College of Cardiology’s 62nd Annual Scientific Session.

Over 4 years, the combination of extended-release niacin and the prostaglandin DP1 antagonist, laropiprant, caused at least one SAE in 31 per 1,000 patients, with no significant benefit observed on “the primary outcome of major vascular events when added to effective statin-based LDL-lowering therapy,” said Jane M. Armitage, BSc, MBBS, MRCP, FFPH, of the Clinical Trial Service Unit, University of Oxford, Oxford, UK, on behalf of the HPS2-THRIVE Collaborative Group.

“We are disappointed that these results did not show benefits for our patients,” said Prof. Armitage. “Still, finding out a drug is not helping people is just as important as finding that it has benefits—the net result is that people are healthier. Niacin has been used for many years in the belief that it would help patients and prevent heart attacks and stroke, but we now know that its adverse side effects outweigh the benefits when used with current treatments.”

Noting these findings are consistent with previous niacin trials, Prof. Armitage added that no clear differences in efficacy or safety were observed in different types of patients, with the known exception of a statin-related myopathy excess in Chinese patients.

After stabilizing 38,369 patients with preexisting occlusive vascular disease on LDL-lowering therapy with simvastatin 40mg ± ezetimibe 10mg daily, the HPS2-THRIVE Collaborative Group initiated a pre-randomization run-in with active extended-release niacin/laropiprant between January 2007 and July 2010. Conducted at 245 hospitals in 6 countries, the study then randomly assigned 25,673 of these patients to extended-release niacin 2g/laropiprant 40mg daily vs. matching placebo in addition to the background LDL-lowering therapy.

Average age of the patients was 64.9 years; 21,229 were men; 14,741 were from Europe and 10,932 were from China. “At randomization, 78% reported coronary disease, 32% cerebrovascular disease, 13% peripheral arterial disease and 33% diabetes,” Prof. Armitage said.

During median follow-up of 4 years, approximately 3,400 participants had a first major vascular event, defined as the composite of non-fatal MI or coronary death, any stroke, and any arterial revascularization; 1,300 were non-fatal MI or coronary death, 1,000 stroke, and 1,700 revascularization; some patients had more than one event. In addition, 1,200 patients developed cancer and 1,500 died, 800 from vascular and 700 from nonvascular causes.

Patients who received extended-release niacin/laropiprant had a similar number of major vascular events compared with those who received placebo (13.2% vs 13.7%; RR=0.96 [95% CI 0.90-1.03]; P=0.29). The study also found unexpected and significant excesses of bleeding (2.5% vs. 1.9%) and infections (8.0% vs. 6.6%) among the patients who received extended-release niacin/laropiprant.

Significantly higher numbers of patients also had new onset diabetes (9.1% vs. 7.3%), diabetic complications (11.1% vs. 7.5%), gastrointestinal problems such as indigestion and diarrhea (4.8% vs. 3.8%), as well as skin SAEs (0.7% vs. 0.4%).

Prof. Armitage said she believes it is unlikely that the trial’s results were due to unexpected side effects of laropiprant in that the observed lack of benefit on MI and stroke is consistent with the recent AIM-HIGH study, which did not use laropiprant. In 2011, AIM-HIGH was halted early when researchers determined a lack of effect for niacin in reducing cardiovascular events.

Extended-release-niacin/laropiprant has been approved in 70 countries and was being sold in 40 countries. The U.S. FDA was awaiting results from HPS2-THRIVE to license the drug. In response to preliminary findings, the drug manufacturer, Merck, announced in December 2012 that it no longer planned to take the drug before the FDA for approval and in January suspended ER niacin/laropiprant from markets worldwide.

Patients taking niacin preparations to prevent heart disease should consider talking with their health care providers to determine whether the therapy is appropriate to continue.