The National Heart, Lung, and Blood Institute has stopped the AIM-HIGH clinical trial 18 months earlier than planned because the addition of high-dose, extended-release niacin has not reduced the risk of cardiovascular events in patients with a history of cardiovascular disease who were taking a statin to lower LDL cholesterol.
At the time the trial was stopped, the yearly rate of cardiovascular events (fatal or nonfatal MI, strokes, hospitalization for acute coronary syndrome, or revascularization procedures) was 5.6% in the control arm and 5.8% in the niacin arm. The news comes from a telebriefing held by the NHLBI on May 26.
"Although high-dose niacin effectively raised the participants’ HDL cholesterol, it did not affect the overall rate of cardiovascular events," said Dr. Susan B. Shurin, acting director of NHLBI.
"The trial was stopped because the data showed that there was a less than 1 in 10,000 chance that the trial would ever show the expected benefit planned in the protocol on the primary outcome measure," added co–primary investigator Dr. Jeffrey Probstfield of the University of Washington, Seattle.
The investigators cautioned nonetheless that individuals who take niacin should not stop without consulting their physician. They also noted that the findings should not alter clinical practice, and should apply only to participants of the AIM-HIGH trial for now.
In late April 2011, the study’s data safety and monitoring board concluded that high-dose, extended-release niacin offered no benefits beyond statin therapy alone in reducing cardiovascular events. The board also noted a small, statistically significant but unexplained increase in ischemic stroke rates in the high-dose, extended-release niacin group.
During the 32-month follow-up period, there were 28 strokes (1.6%) among patients in the niacin group, compared with 12 strokes (0.7%) reported in the control group. In particular, roughly a third (32%) of the strokes in the niacin group occurred in participants who had discontinued the drug at least 2 months and up to 4 years earlier. This finding contributed to the NHLBI acting director’s decision to stop the trial early. Previous studies have not suggested that stroke is a potential complication of niacin. It’s unclear whether this trend seen in this study was due to chance or related to niacin administration or some other issue.
For the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial, researchers enrolled 3,414 participants in the United States and Canada who had a history of cardiovascular disease and who were taking a statin drug to keep their LDL cholesterol levels low. Study participants also had low HDL cholesterol and high triglyceride levels, which meant that they were at significant risk of experiencing future cardiovascular events.
Niacin is known to raise HDL cholesterol and lower triglycerides. Study participants were randomly assigned to either high-dose extended-release niacin (Niaspan) in gradually increasing doses up to 2,000 mg/day (1,718 people) or a placebo treatment (1,696 people). All participants were prescribed simvastatin (Zocor), and 515 participants were given a second LDL cholesterol–lowering drug, ezetimibe (Zetia), in order to maintain LDL cholesterol levels in the target range of 40-80 mg/dL.
Importantly, this trial excluded individuals with acute coronary syndrome and recent MI or percutaneous coronary intervention. The investigators highlighted that the results of this trial apply only to patients in this specific population and can’t be extrapolated to other groups.
Earlier studies of niacin had shown more favorable results. However, the earlier studies were not designed specifically to evaluate the impact of raising HDL cholesterol on the risk of cardiovascular events while maintaining excellent LDL cholesterol control, as in the AIM-HIGH study. Several other trials testing this hypothesis – including a large international trial of high-dose, extended-release niacin – are still ongoing.
The niacin tested in the study is a proprietary formulation manufactured by Abbott Laboratories. The Food and Drug Administration regulates the use of high doses of niacin (more than 500 mg) by prescription for helping treat low HDL cholesterol and/or high triglycerides. At prescription-level doses, flushing can occur. The extended-release formulation of niacin that was tested in AIM-HIGH was intended to help reduce the likelihood of flushing.
All AIM-HIGH study participants have been informed of the results and will be followed for an additional 12-18 months. The study investigators will focus on completing data collection and analysis. The preliminary outcomes of the study are expected to be reported at scientific meetings in the fall of 2011.
The NHLBI funded the AIM-HIGH study with additional support from Abbott Laboratories. Abbott also provided Niaspan, and Merck Pharmaceuticals provided Zocor.