HPS-2 THRIVE Misses Primary End Point: No Benefit of Niacin/Laropiprant

December 20, 2012

WHITEHOUSE STATION, New Jersey — The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) study, a secondary-prevention trial testing the addition of extended-release niacin to statin therapy, has missed its primary end point and shown no clinical benefit for extended-release niacin[1].

After nearly four years of follow-up, the combination of niacin with the antiflushing agent laropiprant did not significantly reduce the risk of the combination of coronary deaths, nonfatal MI, strokes, or coronary revascularizations compared with statin therapy, according to Merck, the sponsor of the HPS-2 THRIVE trial. In a press release announcing the results, Merck said the combination significantly increased the risk of nonfatal but serious side effects.

Merck announced it will no longer be taking the drug before the US Food and Drug Administration to gain approval. The combination of extended-release niacin and laropiprant, known as Tredaptive or Cordaptive, was approved by European regulators in 2008, but Merck is advising doctors from starting any new patients on the drug. One day after the Merck announcement, the Medicines Agency announced that it would be starting a review of the safety and efficacy of Tredaptive, given the results of the HPS-2 THRIVE study [2]. It will make a recommendation to the Committee on Medicinal Products for Human Use (CHMP), and an opinion on any required regulatory action is expected in January 2013.

This is the second major setback for physicians hoping that niacin, a drug that raises HDL-cholesterol levels, might be used clinically to reduce the risk of cardiovascular events. In May 2011, the National Heart, Lung, and Blood Institute (NHLBI)-sponsored  Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes(AIM-HIGH) study, was halted early after showing no benefit of niacin when given in addition to statin therapy.

Coincidentally, a systematic review and meta-analysis by Drs Paul Lavigne and Richard Karas (Tufts Medical Center, Boston, MA) evaluated 11 studies including 9959 subjects, primarily secondary-prevention studies, treated with niacin [3]. The studies included ARBITER-2 and ARBITER-6, as well as the AIM-HIGH study. In the meta-analysis, which is published online December 19, 2012 in the Journal of the American College of Cardiology, treatment with niacin was associated with a significant 34% reduction in the composite end point of any cardiovascular disease event and a significant 25% reduction in coronary heart disease events.

Trial Design Might Have Influenced Results

Dr William Boden (Samuel Stratton VA Medical Center, Albany, NY), the lead investigator of AIM-HIGH, told heartwire that he was disappointed by the results, saying he was hoping the trial would be successful and show a benefit for niacin. While little data are available right now and the press release contains scant information, Boden noted that HPS2-THRIVE was an all-comers secondary-prevention study and did not preselect patients with very low HDL-cholesterol levels.

"The epidemiologic relationship with HDL cholesterol and cardiac events is inverse, but it's inverse curvilinear, meaning that when HDL gets below 40 mg/dL for men and 50 mg/dL and women, there is a signal of increased risk," said Boden. "But the risk really gets steep when you get an HDL below 35 or 30 mg/dL. This is really where you fall off the cliff."

With an all-comers design where baseline HDL-cholesterol levels were 50 mg/dL, for the sake of argument, a 20% increase in HDL with niacin would increase levels to 60 mg/dL, but this is the flat part of the event curve, said Boden. Although powered for clinical events, the improvement in HDL would likely be insufficient to result in a significant reduction in cardiovascular events.

Many Failed HDL-Raising Therapies

The landscape of HDL-raising therapies is now littered with failed therapies, including niacin and the negative results with the cholesteryl ester transfer protein (CETP) inhibitors.

Dr Steve Kopecky (Mayo Clinic, Rochester, MN), the president of the American Society of Preventive Medicine and one of investigators of the AIM-HIGH study, said he was also disappointed by the results, but these trials show just how difficult it is to provide additional benefit when patients are well-treated with statins. In AIM-HIGH, for example, patients were treated with statin therapy anywhere from one to five years. Kopecky noted that observational studies have shown that raising HDL cholesterol with exercise, eating a lower saturated-fat diet, losing weight, stopping smoking, and drinking small amounts of alcohol raises HDL cholesterol and lowers cardiovascular risk.

"Now we always thought that was causative, that HDL going up caused the lower cardiovascular events, but I think it's more appropriate to say it's how the HDL went up that lowered cardiovascular events," Kopecky told heartwire . "We now have a couple of different drug types that raise HDL cholesterol nicely, like niacin and the CETP inhibitors, but those have all crashed and burned when we study them."

Boden noted that the niacin/laropiprant combination was being marketed as early as 2008 in the US, with advertisements in the major medical journals, before the FDA issued a "not-approvable" letter to Merck with regard to the drug. At the time, the FDA wanted more data, data that HPS-2 THRIVE was meant to provide. It was speculated that the agency wanted more data on laropiprant as there were concerns about potential off-target effects.

"Since Merck didn't really know that laropiprant was a clean drug, could there have been some sort of interaction between the laropiprant component of the niacin/laropiprant combination?" asked Boden. "Maybe they should have performed a factorial-designed study, which would have allowed them some way to sort out whether there was an adverse interaction with laropiprant. . . . There was no outcomes data with laropiprant--how could Merck have been so certain that this was a drug that was not going to have unforeseen effects?"

As a result, it remains unknown if the lack of benefit was the result of ineffectiveness when niacin was added to simvastatin or whether the benefit was canceled out as a result of an off-target effect caused by laropiprant.

"Physicians were disappointed with the results of AIM-HIGH, but the skeptics said let's reserve judgment, let's hang in there until we get the results of HPS-2 THRIVE and then we'll make decision," said Boden. "Two negative studies may push practitioners over the niacin cliff, and the use of the drug will decline further. I think it's unfortunate, because I personally am of the opinion that we just have not designed the right trial yet."

Speaking with heartwire , Dr James Stein (University of Wisconsin Medical School, Madison) noted that laropiprant works by blocking DP1 receptors on vascular cells to prevent flushing, but the DP1 receptors are elsewhere in body, including platelets, neurons and respiratory tissue. "We have to be humble whenever we have a drug and we think we know how it works; there is always the possibility there is another target in the human body it's antagonizing," said Stein. He is interested in seeing the full results of the study, as Merck's description of a significant increase in serious nonfatal adverse events is extremely vague.