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NLA Statement on Use of Niacin in Light of HPS2-THRIVE Presentation on March 9, 2013

On March 9, 2013, HPS2-THRIVE results were presented at the American College of Cardiology meeting in San Francisco, after which the presenting author concluded “we now know that [niacin’s] adverse side effects outweigh the benefits when used with current treatments.” The National Lipid Association (NLA) is concerned that this very broad study interpretation does not give adequate consideration to two sharply limiting factors in the trial: 1) niacin was clinically irrelevant in the average study subject, and 2) there was substantial subgroup heterogeneity. The NLA urges caution in extrapolating findings from any unpublished presentation, especially in this case since careful evaluation of these limiting factors in peer-reviewed, published data is needed.

A total of 25,673 subjects from China and five European countries, with prior coronary, cerebrovascular or peripheral arterial disease events (with or without diabetes) were randomized to receive extended-release niacin with a flush-blocking agent laropiprant (ERNL) or placebo on background statin therapy (with or without ezetimibe). The primary composite endpoint of major vascular events (MVE) was not significantly reduced (risk ratio 0.96, 95% CI: 0.90-1.03, p =0.3) in the active arm. “Serious adverse events” were found in 3% more subjects in the active arm, although most were “minor hyperglycemic problems.” Myopathy generally was uncommon (0.34%/yr), but was 4-fold higher overall in the active arm, and 10-fold higher among Chinese subjects.

On average, baseline LDL-C was 63 mg/dL and non-HDL-C about 84 mg/dL, such that subjects were not in need of niacin for lowering these levels. Further, baseline TG was 125 mg/dL and HDL-C was 44 mg/dL, so HPS2-THRIVE tested a drug in patients who, on average, had no indication to take it. Further, MVE reduction with ERNL was strongly predicted by baseline LDL-C (heterogeneity p=0.02), with apparent net benefit if LDL-C was above 58 mg/dL at study entry. Of further concern is the possibility of heterogeneity in MVE response by baseline TG and HDL-C. Four prior fibrate trials (HHS, VA-HIT, FIELD, ACCORD-Lipid), one prescription omega-3 trial (JELIS), and two niacin trials (CDP and AIM-HIGH) all have shown substantially greater cardiovascular disease (CVD) benefit in subjects having both a high TG and low HDL-C at baseline vs. subjects with more normal TG and/or HDL-C levels. Although MVE effects of ERNL in HPS2-THRIVE did not differ in by baseline HDL-C or TG taken separately, analyses of subjects with both low HDL-C and high TG have not been reported. Thus, we do not yet know if HPS2-THRIVE replicates the CVD benefit seen consistently in high TG/low HDL-C patients with niacin or other TG/HDL medications in several prior trials. HPS2-THRIVE showed another key heterogeneity in MVE effects by country. Among HPS2-THRIVE subjects from Europe there was a clinically significant ~10% decrease in MVE with ERNL, while among the 43% of subjects from China, there was a trend towards a ~3% increase in MVE (heterogeneity p=06). Thus, ERNL has net harm in Chinese patients when added to simvastatin. In contrast, however, among Europeans (likely largely Caucasian) there was net MVE benefit, as well as less myopathy. Finally, it remains possible that the use of laropiprant in the niacin arm of the study increased adverse events and/or reduced benefits.

Further analyses of HPS-2-THRIVE will be included in a clinical recommendations paper regarding HDL to be published by the NLA in Fall 2013. Meanwhile, we believe that niacin remains a valuable adjunct to statin treatment for LDL-C lowering, and a valuable statin alternative in statin intolerant patients. Further, in agreement with current NCEP ATP III Guidelines, we believe that niacin should continue to be considered for use as a statin adjunct in patients with persistent low HDL-C and high TG.

As always, the NLA urges patients to seek medical advice from their health care providers, and urges clinicians to customize clinical decisions to individual patient values and circumstances, and best available evidence.

 

HPS2 THRIVE

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Publish Date: 
March 15, 2013 - 12:00pm



by Dr. Radut.