AIM-HIGH trial goes down

The National Heart, Lung and Blood Institute (NHLBI), a division of the National Institutes of Health, has stopped a clinical trial, co-sponsored by Abbott Laboratories, which was studying a blood lipid treatment, 18 months earlier than planned. The trial found that adding high dose, extended-release niacin to statin treatment in people with heart and vascular disease, did not reduce the risk of cardiovascular events, including heart attacks and stroke.

Participants were selected for AIM-HIGH because they were at risk for cardiovascular events despite well-controlled LDL cholesterol. Their increased risk was due to a history of cardiovascular disease and a combination of low HDL cholesterol and high triglycerides.

During the study’s 32 months of follow-up, participants who took high dose, extended-release niacin and a statin had increased HDL cholesterol and lowered triglyceride levels compared with participants who took a statin alone. However, the NHLBI said that the combination treatment did not reduce fatal or non-fatal heart attacks, strokes, hospitalizations for acute coronary syndrome or revascularization procedures.

“Seeking new and improved ways to manage cholesterol levels is vital in the battle against cardiovascular disease,” said Susan B. Shurin, MD, acting director of the NHLBI. “This study sought to confirm earlier and smaller studies. Although we did not see the expected clinical benefit, we have answered an important scientific question about treatment for cardiovascular disease.”

AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health) enrolled 3,414 participants in the U.S. and Canada with a history of cardiovascular disease who were taking a statin drug to keep their LDL cholesterol low.

Study participants also had low HDL cholesterol and high triglycerides. Niacin, also known as Vitamin B3, has long been known to raise HDL and lower triglycerides, according to the NHLBI. Eligible participants were randomly assigned to either high dose, extended-release niacin (Niaspan, Abbott) in gradually increasing doses up to 2,000 mg per day (1,718 people) or a placebo treatment (1,696 people). All participants were prescribed simvastatin (Zocor, Merck Pharmaceuticals), and 515 participants were given a second LDL cholesterol-lowering drug, ezetimibe (Zetia, Merck) to maintain LDL cholesterol levels at the target range between 40-80 mg/dL.

The NHLBI funded the AIM-HIGH study with additional support from Abbott, based in Abbott Park, Ill.

In a statement, Abbot said, “The AIM-HIGH study population does not represent all patient populations in whom the importance of treating low HDL and lowering triglycerides with Niaspan may be significant. Abbott will reflect the relevant study findings in the label after finalization of the AIM-HIGH study results and appropriate review.”

Researchers began recruiting participants in early 2006. The study was scheduled to finish in 2012. The average age of the participants was 64 years. Pre-existing medical conditions included coronary artery disease (92 percent); metabolic syndrome, which is a cluster of risk factors for heart disease (81 percent); high blood pressure (71 percent) and diabetes (34 percent). More than half of participants reported having a heart attack prior to entering the study.

The rationale for the AIM-HIGH study was based in part on a large number of observational studies that consistently showed that low HDL cholesterol increases the risk of cardiovascular events in men and women, independent of high LDL cholesterol.

In addition, previous small clinical studies showed that relatively high residual cardiovascular risk exists among patients with cardiovascular disease, low HDL cholesterol and high triglycerides despite intensive management of LDL cholesterol.

However, efforts to find HDL-raising treatments that actually reduce this residual risk have thus far proved disappointing, the NHBLI reported. Fenofibrate, an HDL-raising drug, failed to reduce the rate of cardiovascular events in patients with diabetes in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial despite favorable effects on HDL and triglycerides.  Another HDL-raising drug, torcetrapib, actually increased the rate of cardiovascular events in the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial despite lowering LDL and triglycerides and raising HDL levels, as intended.

Earlier studies of niacin had shown more favorable results. Unlike AIM-HIGH, the earlier studies were not designed specifically to evaluate the impact of raising HDL on the risk of cardiovascular events while maintaining excellent LDL control. Several other trials testing this hypothesis, including a large international trial of high dose, extended-release niacin, are still ongoing.

At a regularly scheduled meeting on April 25, the study’s data and safety monitoring board (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. For this reason, the DSMB recommended that the NHLBI end the study.

The DSMB also noted a small and unexplained increase in ischemic stroke rates in the high dose, extended-release niacin group. This contributed to the NHLBI acting director’s decision to stop the trial before its planned conclusion. During the 32-month follow-up period, there were 28 strokes (1.6 percent) reported during the trial among participants taking high dose, extended-release niacin versus 12 strokes (0.7 percent) reported 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 strokes. 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, was related to niacin administration or some other issue.

All AIM-HIGH study participants have been informed of the results and will be scheduled for clinic visits within the next 2.5 months, according to the NHLBI. Participants will be followed for an additional 12 to 18 months.

“Patients who were not in the AIM-HIGH trial should not stop taking high dose, extended-release niacin without talking to their doctor first,” said Shurin.

“The lack of effect on cardiovascular events is unexpected and a striking contrast to the results of previous trials and observational studies," said Jeffrey Probstfield, MD, the trial’s co-principal investigator and professor of medicine and epidemiology at the University of Washington in Seattle. "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.”

“The results from AIM-HIGH should not be extrapolated to apply to potentially higher-risk patients such as those with acute heart attack or acute coronary syndromes, or in patients whose LDL cholesterol is not as well-controlled as those in AIM-HIGH,” said William E. Boden, MD, AIM-HIGH’s co-principal investigator and professor of medicine and preventive medicine at the University at Buffalo in N.Y.

The niacin tested in the study is a proprietary formulation used in doses of 500 and 2,000 mg, manufactured by Abbott and approved and regulated by the FDA.

“As we continue to search for new approaches to treating cholesterol problems, it is important to remember the value of existing treatments. The key to treating high cholesterol so patients can reduce their risk of cardiovascular disease is to lower the level of LDL cholesterol, through well-established drug treatments such as statins and lifestyle changes,” said Patrice Desvigne-Nickens, MD, NHLBI project officer for the AIM-HIGH trial.
 
The AIM-HIGH investigators will now focus on completing data collection and analysis. The preliminary outcomes of the study are expected to be reported at scientific meetings this fall.