Orlando, Fla.—The use of statins to reduce LDL-C is more effective with the subsequent addition of extended-release niacin (Niaspan; Abbott), which lowers LDL plus increases HDL, compared with the subsequent administration of ezetimibe (Zetia; Merck) in reducing the progression of atherosclerosis, according to the ARBITER 6-HALTS trial presented Monday at the American Heart Association (AHA) conference.
During the late-breaking clinical trial session, principal investigator Allen J. Taylor, MD, presented the ARBITER 6-HALTS trial, an open-label study comparing two separate treatment strategies—whether raising HDL-C with niacin or lowering LDL-C with ezetimibe could show a difference on carotid intima-media thickness (CIMT). The primary end point was the between-group difference in the change from baseline in the mean common CIMT after 14 months.
In 2008, approximately nine million U.S. patients received treatment with ezetimibe and approximately 2.5 million U.S. patients received niacin.
The researchers enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women had been achieved. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day).
According to Taylor, they selected patients with an HDL threshold that was representative of the U.S. population median values, as opposed to a “classically low HDL population.” The trial’s patient population comprised 80 percent male, overall average age was 65 and all patients were on statins (95 percent were taking simvastatin or atorvastatin).
The trial was terminated early, on the basis of efficacy, according to a pre-specified analysis conducted after 208 patients had completed the trial.
Taylor and colleagues found that niacin was superior to ezetimibe for the change in mean and maximal CIMT at both eight and 14 months. Also, there was “significant regression in mean and maximal CIMT at both eight and 14 months,” Taylor reported.
With the ezetimibe group, Taylor reported no net changes in CIMT. Also, the researchers found a significant inverse relationship between change in LDL-C and the change in CIMT in the ezetimibe group.
In his commentary of the trial, John J.P. Kastelein, MD, PhD, from the department of vascular medicine at the Academic Medical Center in Meibergdreef, the Netherlands, said that published data on the relationship between the change in LDL and CIMT reported in the SANDS trial is at variance with ARBITER 6-HALTS.
Also, as former principal investigator of the ENHANCE trial, Kastelein noted that he and his colleagues opened the ENHANCE database to see if this finding was also true, and they did not find the same results.
Taylor also reported that major adverse cardiovascular events occurred at a nearly significant higher incidence in the ezetimibe group compared with the niacin arm (5.5 vs. 1.2 percent).
Based on their findings, Taylor concluded that the combination therapy of statin-niacin is superior to statin-ezetimibe. He added that “prudent clinical practice presently favors avoidance of ezetimibe because its net effect on clinical outcomes is unknown, and now its relative effectiveness is known to be inferior.” Yet, he also added that clinicians need to understand how to use niacin.
However, Kastelein, who also wrote an editorial in the New England Journal of Medicine about the trial, deemed the early termination of the study “unfortunate,” and suggested that the results may be an “overestimation of the real between-group difference owing to chance, that may not persist over time.”
Also, Kastelein, who disclosed that he has received consulting and lecturing fees from Merck, criticized the design of the post-hoc ARBITER 6-HALTS study for assessing the relationships by using single-variable correlation coefficient, as opposed to statistical modeling. “Such an approach is not the most rigorous in the current, evidence-based era. Post-hoc analyses are very sensitive to bias due to confounding,” he said.
Kastelein also noted that future trials will evaluate the role of niacin in reducing clinical events in patients with cardiovascular disease, including: AIM-HIGH and HPS2-THRIVE.
Abbott Laboratories of Abbott Park, Ill., sponsored