May 26, 2011 (Bethesda, Maryland) — A trial of extended-release niacin (Niaspan, Abbott) given in addition to statin therapy in patients with a history of cardiovascular disease, high triglycerides, and low levels of HDL cholesterol has been halted prematurely, 18 months ahead of schedule, because niacin offered no additional benefits in this patient population .
There was also a small, unexplained increase in ischemic stroke in the high-dose, extended-release niacin group, in the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study, according to a statement from the National Heart Lung and Blood Institute (NHLBI), which sponsored it.
Despite treatment with statin therapy for elevated LDL-cholesterol levels, those with low levels of HDL cholesterol remain at significant risk for cardiovascular events, and AIM-HIGH was designed to examine whether raising HDL using extended-release niacin would be beneficial in such patients. AIM-HIGH was a five-year study of almost 3500 patients, and results were originally expected in September 2012.
The decision to stop the trial was made at a regularly scheduled meeting of the study's independent data and safety monitoring board (DSMB) on April 25, 2011. The DSMB concluded that "high-dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular-related complications in this trial. The rate of clinical events was the same in both treatment groups, and there was no evidence that this would change by continuing the trial."
Patients Should Not Stop Taking Niacin
The NHLBI explains that the rationale for AIM-HIGH was based on data from observational studies and a few small clinical studies. "This study sought to confirm earlier and smaller studies," says Dr Susan B Shurin (acting director of the NHLBI) in the statement. "Although we did not see the expected clinical benefit, we have answered an important scientific question about treatment for cardiovascular disease.”
Several other trials testing this hypothesis, including a large international trial of high-dose, extended-release niacin, the Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), are still under way; results of HPS2-THRIVE are expected in 2013. Extended-release formulations of niacin are being used in these trials because the immediate-release form of niacin is associated with a high incidence of flushing.
Previous studies do not suggest that stroke is a potential complication of niacin, and it remains unclear whether this trend in AIM-HIGH arose by chance or was related to niacin administration or some other issue, says the NHLBI. "Patients who were not in the AIM-HIGH trial should not stop taking high-dose, extended-release niacin without talking to their doctor first," says Shurin.
All AIM-HIGH study participants have been informed of the results and will be scheduled for clinic visits within the next 2.5 months. Participants will be followed for an additional 12 to 18 months.
AIM-HIGH co–principal investigator Dr Jeffrey Probstfield (University of Washington, Seattle) said: "The lack of effect on cardiovascular events is unexpected and a striking contrast to the results of previous trials and observational studies. The AIM-HIGH findings do not support the trial’s hypothesis that, in the population studied, adding extended-release niacin to simvastatin in participants with well-controlled LDL cholesterol can provide additional clinical benefit.”
AIM-HIGH enrolled 3414 participants in the US and Canada with a history of cardiovascular disease, low HDL cholesterol, and high triglycerides, who were all prescribed simvastatin and who were also randomized to either high-dose, extended-release niacin in gradually increasing doses up to 2000 mg per day (n=1718) or placebo (n=1696). Of the participants, 515 were given a second LDL-cholesterol–lowering drug, ezetimibe (Zetia, Merck/Schering-Plough), in order to maintain LDL-cholesterol levels at the target range between 40 and 80 mg/dL.
Participants who took high-dose, extended-release niacin and statin treatment had increased HDL cholesterol and lowered triglyceride levels than participants who took a statin alone. However, the combination treatment did not reduce fatal or nonfatal MI, strokes, hospitalizations for acute coronary syndrome, or revascularization procedures.
During the 32-month follow-up period, there were 28 strokes (1.6%) reported among participants taking high-dose, extended-release niacin vs 12 strokes (0.7%) in the control group. Nine of the 28 strokes in the niacin group occurred in participants who had discontinued the drug at least two months and up to four years before their stroke.