SAN FRANCISCO—A combination of the vitamin niacin with laropiprant demonstrates no benefit to and may even be harmful for patients with vascular disease, based on the HPS2-THRIVE late-breaking trial presented March 9 at the American College of Cardiology’s (ACC) scientific session. “These findings definitely hammer more nails into the coffin of niacin,” said study panelist Spencer B. King III, MD, who also questioned whether there still may be a subset of patients for whom niacin could be effective.
“What about those patients who have less control of their LDL [low-density lipoprotein]? Could they benefit from the addition of other drugs?” King, chair of interventional cardiology at the Fuqua Heart Center of Piedmont Hospital in Atlanta, questioned during a press conference.
The niacin/laropiprant combination (Tredaptive, Merck) raises HDL-cholesterol and reduces LDL-cholesterol (as well as Lp(a) and triglycerides). Laropiprant (Merck) is a prostaglandin DP1 antagonist that reduces niacin-induced flushing.
In this study, Jane Margaret Armitage, FFPH, FRCP, of University of Oxford in Oxford, England, and colleagues sought to assess whether adding niacin to statin-based LDL-lowering therapy safely produces worthwhile reductions in major cardiovascular outcomes.
Between January 2007 and July 2010, they included 38,369 patients with pre-existing occlusive vascular disease at 245 hospitals from six countries (four Scandinavian countries, the U.K. and China) who started a pre-randomization run-in with active ER niacin/laropiprant after stabilization on LDL-lowering therapy with simvastatin 40mg with or without ezetimibe 10mg daily.
Of these patients, the researchers randomly allocated 25,673 patients to ER niacin/laropiprant 2g/40mg (ERN/LRPT) daily versus matching placebo in addition to the background LDL-lowering therapy. The population was of average age of 65 years, with 21,229 men and 4,444 women. Also, 14,741 were from Europe and 10,932 from China.
At randomization, 78 percent reported coronary disease, 32 percent cerebrovascular disease, 13 percent peripheral arterial disease and 33 percent diabetes. The primary study endpoint was time to first major vascular event, defined as the composite of non-fatal MI or coronary death, any stroke or any arterial revascularization.
During a median follow-up of four years, patients receiving ER niacin/laropiprant had a similar number of major vascular events as patients receiving placebo (13.2 vs. 13.7 percent). Also, approximately 3,400 participants had major vascular events (1,300 non-fatal MI or coronary death; 1,000 strokes; 1,700 revascularizations; with some having more than one such event), 1,200 have developed cancer and 1,500 have died (800 vascular and 700 non-vascular causes).
“We did see the expected, small increase in HDL cholesterol with the ER niacin preparation of 6 mg/dL, and a decrease in LDL of 10 mg/dL,” reported Armitage. “These are quite small changes in comparison to statin therapy, for example, as we expected 10-15 percent benefit.”
The study also found unexpected and significant excesses of bleeding (2.5 vs. 1.9 percent) and infections (8 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).
There was a significant excess in serious adverse events in those taking ER niacin/laropiprant—meaning every 30 in every 1,000 experienced at least one of these events.
“We are disappointed that these results did not show benefits for our patients,” said 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.”
Armitage added that the size and scope of HPS2-THRIVE make its findings about niacin’s outcomes and side effects reliable. “In the light of these findings, ER niacin for the cardiovascular risk presentation needs to be reconsidered,” she concluded.
King questioned its role in patients who have less control of their LDL, but Armitage seemed less convinced of this, due to the potential harms.
ER niacin/laropiprant has been approved in 70 countries and was being sold in 40. The FDA 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.