The Shaky Role for Niacin in Secondary Prevention

Patrice Wendling

April 29, 2019

Already relegated to the periphery of clinical practice, a new meta-analysis calls for a federal committee to reconsider a residual indication for extended-release niacin monotherapy in secondary prevention.

The analysis showed no preventive association for niacin with cardiovascular disease (CVD) outcomes among 35,760 patients with established coronary disease, atherosclerosis, or dyslipidemia in 17 randomized trials conducted through 2017.

Among those not taking statins, however, niacin monotherapy was associated with a lower risk for acute coronary syndrome (risk ratio [RR], 0.74; 95% CI, 0.58 - 0.96), stroke (RR, 0.74; 95% CI, 0.59 - 0.94), and revascularization (RR, 0.51, 95% CI, 0.37 - 0.72).

The results suggest niacin may be a "reasonable clinical choice" in patients intolerant to statins or wanting to avoid potential drug–drug interactions, but are based on a target population that may not be generalizable to today's patients, the authors say.

The results were drawn from two trials conducted decades ago — the 1975 Coronary Drug Project, which was the main reference in labeling for niacin monotherapy in secondary prevention in the United States, and the 1988 Stockholm Ischaemic Heart Disease Secondary Prevention Study.

The arrival of stains in the ensuing years and more widespread use of aspirin, antiplatelet therapy, beta blockers, and renin-angiotensin system inhibitors after a myocardial infarction (MI) also might have changed the underlying CV risk, even among patients not taking statins, and "reduced the marginal benefit that niacin might provide for contemporary patients," they note.

Therefore, the US Food and Drug Administration (FDA) should "convene an advisory committee to reconsider this approved indication for niacin products, leading to a new trial, perhaps funded by the National, Heart, Lung, and Blood Institute, to confirm that it remains relevant," write lead author Elvira D'Andrea, MD, MPH, Brigham and Women's Hospital, Boston, and colleagues in their meta-analysis, published online April 12 in JAMA Network Open.

It was a very well-done analysis but "I remain bothered by the fact there continues to be a fair deal of niacin bashing," William Boden, MD, lead investigator of the AIM-HIGH trial and professor of medicine, Boston University School of Medicine, said in an interview.

Boden argues the issue of niacin in CV event reduction remains unsettled, citing design flaws in the 2011 AIM-HIGH and 2014 HPS2-THRIVE trials. The lack of clinical effectiveness seen in the two trials shifted the role of niacin in practice and, in the meta-analysis, pushed a preventive association for niacin with CV outcomes toward the null since 2011.

In AIM-HIGH, however, 75% of patients receiving blinded treatment were taking statins or other lipid-lowering agents for 3 to 5 years, and the placebo tablets contained a small 50 mg-dose of immediate-release niacin, he said. HPS2-THRIVE enrolled patients with normal high-density lipoprotein cholesterol (HDL-C), and the extended-release niacin preparation included the prostaglandin inhibitor laropiprant, which may have had a neutralizing effect on the niacin.

"The problem is we haven't had the right designed trial and, you could argue, we haven't had the right intervention," Boden said. "I would still say the jury is out on whether we have conclusively demonstrated that niacin is of no clinical benefit in patients with cardiovascular disease."

Substantial Adverse Effects

Jane Armitage, MD, lead investigator of HPS2-THRIVE and professor of clinical trials and epidemiology, University of Oxford, United Kingdom, told | Medscape Cardiology via email that, "in my view, there is no therapeutic role for niacin in current clinical practice."

"In the HPS2-THRIVE trial, we were unable to find a group of patients for whom possible benefits would outweigh the risks," she said. "For patients who need lipid-lowering medication and who will not or cannot take a statin, there are safer and more effective alternative medications, such as ezetimibe and PCSK9 inhibitors."

Armitage notes there is no evidence of benefits from niacin in today's patients who are on statins and good evidence of harms, which are barely mentioned in the report. Despite including data from HPS2-THRIVE, it fails to note "the substantial and highly significant increases in the risk of diabetes, infections, and bleeding with niacin seen in the trial." These are in addition to the mentioned adverse effects on the gastrointestinal tract and skin rashes.

"For the reasons outlined above (i.e., that niacin is associated with substantial side effects), I believe the FDA should reconsider its indication for niacin, as has been done in Europe," she said.

The authors suggest that over-the-counter use of niacin for cardioprotection is an additional concern, as "any incremental benefits of niacin as monotherapy become even more indeterminate," especially as the dosage is substantially lower than administered in clinical trials. "This inappropriate use might also be associated with an increase in the risk of adverse events without an improvement in outcomes," they write.

Armitage sais she has major concerns about people being able to buy niacin over the counter in doses sufficient to have lipid-modifying effects because the adverse effects can be serious and hard to predict.

HDL Hypothesis Takes a Hit

"Our findings add further evidence against the clinical hypothesis that increasing HDL-C levels may play a key part in modifying cardiovascular risk," write D'Andrea and colleagues.

"With our stratified analysis, we were able to show that when the LDL-C level is corrected using statins, there is no evidence that adding niacin provides incremental clinical benefit, which in such a clinical scenario should be mainly because of its ability to increase HDL-C levels," they say.

Moreover, meta-regression using data from 14 of the 17 studies showed that change in HDL-C levels was not associated with the log risk ratio for the primary CV outcomes of CVD and coronary heart disease mortality, acute coronary syndrome, stroke, revascularization, or major adverse cardiac events.

Although acknowledging being in the minority still supporting the HDL hypothesis, Boden said he is deeply concerned by the total dismissiveness of HDL cholesterol as a risk-treatment variable. He also spoke out against the steadfast use of 40 mg/dL in men and 50 mg/dL in women as the cut point for normal HDL-C levels, despite a progressive decline in what is considered the normal range for low-density-lipoprotein cholesterol (LDL-C) and triglycerides.

"I continue to see, every week, patients who have LDL below 70 or even 50 on high-intensity statins who are back again with another cardiovascular event or acute coronary syndrome, and a certain percentage of them — 20% to 30% — have really low HDLs below 30, but everybody ignores it," Boden said.

He noted that an AIM-HIGH post hoc analysis showed niacin was associated with a significant, though nominally, decreased primary event rate among the roughly 16% of patients in the lowest HDL tertile (<32 mg/dL) and highest triglyceride tertile (>198 mg/dL). This phenotype, which is present in the increasing population of patients with diabetes, may be a target subset for the coadministration of niacin or other drugs.

"I do believe the data support a reduction of myocardial infarction," Boden said. "So I don't know what is to be gained by driving the last nail in the coffin, so to speak, to really basically take the drug off the market where I still think there is a niche for the drug and, potentially, it could be larger than a niche."

"I'm simply pleading for keeping an open mind about this," he said. "Fifty years of epidemiology can't be completely wrong and, when I say that, I mean there is just abundant epidemiology to support the fact that low HDL is an independent predictor of bad outcomes."

The study was funded by the Laura and John Arnold Foundation. D'Andrea, Boden, and Armitage have reported no relevant conflicts of interest.

JAMA Netw Open. Published online April 12, 2019. Full text

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