Niacin fails to further improve outcomes when added to statin
MedWire News: Adding extended-release niacin to simvastatin therapy offers no incremental improvement in cardiovascular outcomes when used for the secondary prevention of cardiovascular disease in people with low levels of high-density lipoprotein (HDL) cholesterol, research shows.
The findings come from the AIM-HIGH (Atherothrombosis Intervention in Metabolic syndrome with low HDL/High triglycerides and Impact on Global Health outcomes) trial, which was stopped for a lack of efficacy and an unexpected increase in ischemic strokes after a median follow-up of 3 years.
Results were presented by the co-principal investigator, William Boden (University of Buffalo, New York, USA) at the American Heart Association Scientific Sessions in Orlando, Florida, USA.
AIM-HIGH compared the addition of high-dose extended-release niacin or placebo to intensive LDL-lowering therapy with a statin, with or without ezetimibe, in patients with atherosclerotic cardiovascular disease and low baseline HDL levels.
Patients were aged 45 years and older, and had vascular disease (coronary heart disease, cerebrovascular disease, or peripheral arterial disease) and dyslipidemia (baseline HDL <40 mg/dL [1.03 mmol/L] for men, <50 mg/dL [1.29 mmol/L] for women, triglycerides from 150-400 mg/dL [1.69-4.52 mmol/L], and LDL <180 mg/dL [4.66 mmol/L]).
Patients first underwent an open-label niacin run-in of 4 to 8 weeks. Those able to tolerate a dose of 1500 mg/day or higher were randomized to receive either extended-release niacin plus simvastatin 40-80 mg/day, adjusted to a LDL target of 40-80 mg, or placebo plus targeted simvastatin.
Placebos were spiked with small doses of niacin, enough to generate the characteristic niacin flush and thus disguise the nature of the pill, said Boden.
At the end of the study period there was no significant difference in the primary endpoint, a composite of CHD death, non-fatal MI, ischemic stroke, hospitalization for ACS, or symptom-driven revascularization. The endpoint was met by 16.4% of the niacin group versus 16.2% of the placebo group, giving a hazard ratio (HR) of 1.02.
In addition, there were no significant differences in certain secondary endpoints, including composites of CHD death, MI, ischemic stroke, or high-risk ACS (HR=1.08) and of CHD death, MI, or ischemic stroke (HR=1.13).
However, there was an unexpected increase in ischemic strokes in the niacin group. This, together with an interim analysis showing that the boundary for inefficacy had been crossed, led the data and safety monitoring board to recommend halting the trial. In the final data analysis, however, the incidence of stroke was not significantly different between the treatment groups.
Seeking to explain why niacin did not show an additional benefit, Boden noted that 94% of patients had previously received statins and 20% of patients had received niacin, which may have limited their ability to show a treatment effect. Additionally, patients on placebo had an unexpected increase in HDL, which might have minimized the between-group differences.
The invited discussant Phillip Barter (Heart Research Institute, Sydney, Australia) criticized the trial design, challenged the decision to halt the trial early, and said that the results should not change practice regarding the use of niacin in patients with low LDL cholesterol.
"This trial disturbs me greatly - not because the results are different from all previous niacin trials, because that happens - but it disturbs me as such because in no way could it test the hypothesis of raising HDL or the benefit of niacin," he said.
Barter also said that the event-driven trial was designed to have an 85% power to detect a 25% reduction in events, adding that to adequately detect such an effect, a much larger sample size or much longer follow-up would be required.
"Whatever conclusions are drawn from this trial, it cannot be emphasized too much that it has NOT tested the HDL hypothesis, nor was it powered to sufficiently test the potential benefits of niacin," he said.
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By Neil Osterweil