A highly anticipated study evaluating a combination of the vitamin niacin with the anti-flushing agent laropiprant finds the therapy provides no benefit to and may even be harmful for patients with vascular disease, according to research presented today at the American College of Cardiology's 62nd Annual Scientific Session. Detailed trial data is presented here for the first time.
Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) is the largest-ever study of niacin, commonly used to raise high-density lipoprotein (HDL) or "good" cholesterol and lower low-density lipoprotein (LDL) or "bad" cholesterol. The four-year study tested a combination of extended-release (ER) niacin with laropiprant in patients at risk for cardiovascular problems such as heart disease and stroke. The 25,673 patients in the study were randomized to receive ER niacin/laropiprant 2g/40mg or a placebo, and all received commonly prescribed LDL cholesterol-lowering medication simvastatin (with or without ezetimibe). The study did not meet the primary endpoint of reducing the chances of a major vascular event, defined as the composite of non-fatal heart attack or heart-related death, stroke, or need for angioplasty or bypass surgery. Patients receiving ER niacin/laropiprant had a similar number of major vascular events as patients receiving placebo (13.2 vs. 13.7 percent, p=0.29).
The study also found unexpected and significant excesses of bleeding (2.5 vs. 1.9 percent) and infections (8.0 vs. 6.6 percent) among the ER niacin/laropiprant patients. In addition, significantly higher numbers of patients receiving the study drug suffered serious known side effects including new onset diabetes (9.1 vs. 7.3 percent), diabetic complications (11.1 vs. 7.5 percent), gastrointestinal problems such as indigestion and diarrhea (4.8 vs. 3.8 percent), and skin issues including itching and rashes (0.7 vs. 0.4 percent).
"We are disappointed that these results did not show benefits for our patients," said Jane Armitage, FFPH, FRCP, professor at the University of Oxford and the lead author of the HPS2-THRIVE study. "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."
A high level of LDL cholesterol is a known risk factor for heart disease and stroke. Standard treatment for at-risk patients includes dietary and lifestyle changes, as well as commonly prescribed medications such as statins, cholesterol absorption inhibitors and resins. Still, heart disease and stroke continue to cause death and disability even in patients receiving these medications, notes Dr. Armitage, and there was hope that the addition of niacin to standard therapy would improve patient outcomes.
Niacin is a type of B-vitamin, but the therapeutic doses used to control cholesterol are about 100 times higher than the amount recommended as part of daily intake. Laropiprant was added to reduce the facial flushing caused by niacin. While there was some speculation that the trial's results may have been due to unexpected side effects of laropiprant, Dr. Armitage believes this is unlikely, as the lack of benefit on heart attacks and strokes is consistent with the recent AIM-HIGH study, which did not use laropiprant, and many of the side effects are known to be due to niacin.
In 2011, AIM-HIGH was halted early when researchers determined a lack of effect for niacin in reducing cardiovascular events. Some experts in the field dismissed AIM-HIGH's findings because of its smaller size and perceived lack of ability to demonstrate definitive outcomes. Dr. Armitage notes that the size and scope of HPS2-THRIVE make its findings about niacin's outcomes and side effects reliable.
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.
ER niacin/laropiprant has been approved in 70 countries and was being sold in 40. The Food and Drug Administration was awaiting results from HPS2-THRIVE to license the drug in the U.S. 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.
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