Time for Niacin to Be ‘Relegated to Medical History’ as HPS2-THRIVE Analysis Confirms Drug’s Failings


Adding extended-release niacin and laropiprant to background statin therapy significantly reduces quality of life-adjusted survival and increases hospital costs, according to a new analysis of the Heart Protection Study 2—Treatment to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial.

Mean survival time over the 4-year treatment period was roughly equal among patients treated with extended-release niacin and laropiprant (an agent added to reduce niacin-related flushing) and those treated with a placebo. However, when investigators factored in other serious adverse events associated with niacin in HPS2-THRIVE, health-related quality-adjusted life-years (QALYs) were significantly lower among those treated with niacin and laropiprant (mean difference -0.023 QALYs with niacin/laropiprant; P < 0.001).

Lead researcher Borislava Mihaylova, DPhil (University of Oxford, England), told TCTMD the niacin/laropiprant combination was associated with numerous serious adverse events in the clinical trial, including diabetes, infections, gastrointestinal effects, and bleeding, and that these events also impact quality of life. As a result, the impact of niacin on survival adjusted for quality-of-life was more pronounced than on survival alone.

“This is only over 4 years, so obviously the impact could be much larger if extrapolated over the longer term,” said Mihaylova. The analysis showed similar reductions in QALYs among patients at all levels of cardiovascular risk, including those with the highest risk of cardiovascular disease, she added. “You’d expect these would be the people most likely to benefit from any positive effects on cardiovascular events, yet we didn’t see anything there either.”

For Jane Armitage, MD (University of Oxford), one of the lead HPS2-THRIVE investigators and a co-author of the latest analysis, any role for niacin in clinical practice is essentially minimal to nonexistent.

“I think if it has a role, it’s extremely limited, maybe in people with very high LDL cholesterol levels who really weren’t able to take any of the other effective medications,” Armitage told TCTMD. “But we now have a range of other effective cholesterol-lowering agents, and I don’t think one would ever need to resort to an old drug that really has substantial harms associated with its use. So, I think there really is no role for niacin in current practice. That would be my view.”

Brendan Everett, MD (Brigham and Women’s Hospital, Boston, MA), who was not involved in the analysis, made a similar assessment. “What you do in medicine is you either try to make people feel better or live longer, and hopefully it’s some combination of both,” he told TCTMD. “Niacin appears to do neither, so there is very little reason to prescribe it. Occasionally I will see patients in consultation for the first time, and if they’re still on niacin just about the first thing I do is to take them off it.”  

The study was published online July 12, 2016, in Circulation: Cardiovascular Quality and Outcomes.

HPS2-THRIVE and AIM-HIGH Answered the Niacin Question

The latest findings are not entirely surprising, given the overall negative results from HPS2-THRIVE. Presented in 2013, the study randomized 25,673 statin-treated patients with a history of vascular disease to treatment with long-acting niacin and laropiprant or placebo. The addition of niacin/laropiprant failed to significantly reduce the risk of vascular events in this group of high-risk patients.

Similarly, the National Heart, Lung, and Blood Institute-funded Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study also failed to show any benefit with extended-release niacin. Among 3,414 patients with established cardiovascular disease, low HDL cholesterol, and high triglycerides, adding niacin had no clinical effect on the study’s primary endpoint, a composite of coronary heart disease death, nonfatal MI, stroke, hospitalization for ACS, or revascularization.

In 2013, the European Medicines Agency withdrew niacin/laropiprant in the European Union, warning physicians they should no longer prescribe the drug, and withdrew other niacin-containing products. This past April, the US Food and Drug Administration withdrew the indication of extended-released niacin when used in combination with a statin and withdrew two niacin-statin combination drugs, Advicor and Simcor (AbbVie), which paired niacin with lovastatin and simvastatin, respectively.

To TCTMD, Armitage said that “niacin is not really used in Europe currently,” she’s aware the drug is still being used in the United States. In an editorial, Harlan Krumholz, MD (Yale School of Medicine, New Haven, CT), notes that long-acting niacin has been a blockbuster drug for a long time, with its use in the US increasing nearly 200% between 2002 and 2009. In December 2009, there were approximately 696,000 niacin prescriptions written per month. However, as HPS-2-THRIVE, AIM-HIGH, and other analyses of clinical trials have now made clear, the use of niacin does not improve clinical outcomes, he writes.

As part of their analysis, Mihaylova and Armitage also examined the increased costs associated with niacin/laropiprant. During the 4-year follow-up period, the mean excess hospital costs per participant was approximately £101 (or $145 USD), a difference that was statistically significant.

For Everett, he said physicians are aware niacin is associated with significant side effects and that many patients do not tolerate it very well, or must go to great lengths to tolerate it. While some might have felt the benefits outweighed the risks, “HPS-2-THRIVE and AIM-HIGH answered that question,” he said. “There is no reason to take something if it makes you feel poorly, doesn’t reduce your risk of heart attack, stroke, or cardiovascular death, and might have other important side effects beyond just flushing.”   

In his editorial, Krumholz notes that the “impulse of many practitioners is to treat laboratory values,” but the outcomes studies with niacin have shown the agent “should be relegated to medical history.”

To TCTMD, Everett agreed about the need to treat patients and their overall risk of cardiovascular events rather their laboratory values, noting that niacin is not alone in its failure to reduce clinical events despite promising changes in lipid numbers. For example, there was a 16% reduction in LDL cholesterol levels in HPS2-THRIVE. Three cholesteryl ester transfer protein (CETP) inhibitors have also failed in large outcomes trials even though those agents dramatically raised HDL cholesterol levels.

 


 

 

 

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Sources
  • Kent S, Haynes R, Hopewell JC, et al. Effects of vascular and nonvascular adverse events and of extended-release niacin with laropiprant on health and healthcare costs. Circ Cardiovasc Qual Outcomes. 2016;Epub ahead of print.

  • Krumholz HM. Niacin: time to believe outcomes over surrogate outcomes. If not now, when? Circ Cardiovasc Qual Outcomes. 2016;Epub ahead of print.

Disclosures
  • HPS2-THRIVE was funded by Merck, UK Medical Research Council, British Heart Foundation, and Cancer Research UK.
  • Mihaylova, Armitage, and Everett report no disclosures.
  • Krumholz reports research agreements with Medtronic and Johnson &amp; Johnson through Yale University. He chairs a cardiac scientific advisory board for United Health.

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