Addition of Extended-Release Niacin/Laropiprant to Statin-Based Therapy Increases Risk of Serious Adverse Events and Does Not Decrease Risk of Major Vascular Events in Patients With Vascular Disease

EBM Focus - Volume 9, Issue 31

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Reference: N Engl J Med 2014 Jul 17;371(3):203 (level 1 [likely reliable] evidence)

For several decades, observational studies have shown correlations between certain lipid markers and risk of major vascular events. Several of these markers have been evaluated as potential targets for the prevention or management of vascular disease. Niacin (also called nicotinic acid or vitamin B3) is an essential human nutrient that increases high density lipoprotein (HDL) cholesterol concentrations through several different mechanisms. Improvements in clinical outcomes in patients at risk of cardiovascular disease have been demonstrated with reduction in low density lipoprotein (LDL) cholesterol concentration. However, although increased HDL cholesterol concentrations are correlated with lower risk of vascular events in observational studies, it has remained unclear whether the addition of niacin to statin-based therapy actually helps decrease the risk of major vascular events. A recent large randomized trial evaluated the addition of a combination of niacin and laropiprant (a prostaglandin inhibitor used to prevent flushing) in patients with vascular disease receiving statin-based therapy.

A total of 42,424 patients aged 50-80 years with a history of myocardial infarction, cerebrovascular disease, peripheral arterial disease, or diabetes entered an unblinded run-in period with simvastatin followed by added ezetimibe if necessary until LDL cholesterol-lowering therapy was standardized, plus extended-release niacin/laropiprant. Afterwards, 25,673 patients without clinically significant adverse events during run-in continued statin therapy and were randomized to extended-release niacin/laropiprant 2 g/40 mg per day orally vs. placebo. The primary outcome was major vascular events, defined as a composite of nonfatal myocardial infarction, coronary-related death, stroke, and arterial revascularization. During median 3.9 years follow-up, the rate of major vascular events was 13.2% with extended-release niacin-laropiprant vs. 13.7% with placebo (not significant). In addition, extended-release niacin-laropiprant was associated with an increased rate of fatal or nonfatal serious adverse events compared to placebo (55.6% vs. 52.7%, p < 0.001, NNH 34). The increased serious adverse events with niacin/laropiprant included infections, gastrointestinal bleeding, disorders of glucose metabolism, and other events associated with gastrointestinal, respiratory, or musculoskeletal systems. Extended-release niacin-laropiprant was also associated with a nonsignificant increase in all-cause mortality compared to placebo (6.2% vs. 5.7%, p = 0.08).

The findings from this new trial are also consistent with those of the AIM-HIGH trial, which also found no reduction in vascular events with extended-release niacin compared to placebo in patients receiving statin therapy (N Engl J Med 2011 Dec 15;365(24):2255). Furthermore, this new trial showed that the use of combination niacin/laropiprant increases the rate of adverse events. In addition, the adverse event rate observed in this trial underestimates the true adverse event rate associated with treatment, since patients experiencing adverse events during the unblinded run-in period were excluded from the trial. It is noteworthy that many adverse events observed in the new trial, including infection and gastrointestinal bleeding, were not expected based on previous studies evaluating niacin such as AIM-HIGH, and may be associated with laropiprant as opposed to niacin itself. As well, it is noteworthy that in this trial, although niacin/laripoprant was associated with substantially increased HDL cholesterol concentrations, the baseline HDL cholesterol levels were not substantially below the normal threshold (about 44 mg/dL in each group). Thus the interpretation of these findings is less clear for patients with low or very low HDL cholesterol levels –the population towards which niacin treatment is primarily targeted.

Collectively, the current evidence shows no evidence of benefit (through effects on HDL concentrations or otherwise) and an increased rate of adverse events with extended-release niacin in this patient population. Combination niacin/laropiprant has not been approved by the U.S. Food and Drug Administration, and has had its marketing authorization withdrawn by the European Medicines Agency based on the results of this new trial (EMA press release).

For more information see the Niacin topic in DynaMed.