This study presents the final results of the ARBITER 6-HALTS Trial, which compared the effects of extended-release niacin (ERN) versus ezetimibe on carotid intima-media thickness (CIMT) when added to statin therapy in patients with cardiovascular risk factors. The study found that while both ERN and ezetimibe reduced LDL-C levels, only ERN led to regression of CIMT, with greater cumulative exposure to ERN through higher adherence and dosage associated with greater CIMT reduction. In contrast, higher cumulative exposure to ezetimibe was linked to CIMT progression. Thus, the trial confirms the superiority of ERN over ezetimibe in

1. The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects
of Reducing Cholesterol 6_HDL and LDL Treatment Strategies in Atherosclerosis): Final
Results and the Impact of Medication Adherence, Dose, and Treatment Duration
Villines et al J. Am. Coll. Cardiol 2010;55:2721-2726
SUMMARY
Introduction. Despite significant reductions in major cardiovascular events, lipid
abnormalities and residual risk in patients receiving statin monotherapy are prevalent. The
authors had previously conducted a comparative-efficacy trial (ARBITER 6-HALTS trial),
examining the addition of ezetimibe or extended-release niacin (ERN) on carotid intima-
media thickness (CIMT) in high-risk patients on stable, chronic statin monotherapy. They
found that ERN leads to a significant regression of CIMT and was superior to ezetimibe
when added to chronic statin therapy.
This study presents the results on final CIMT imaging among the full trial sample of the
ARBITER 6-HALTS trial. In addition, here the authors analyze the effect on CIMT of study
medication adherence, dose optimization, and treatment duration.
Methods:
The inclusion criteria mandated for patients was: know atherosclerotic cardiovascular
disease or coronary heart disease equivalent, currently taking statin monotheraphy at a
consistent dose. Low-density lipoprotein cholesterol (LDL-C ) <100 mg/ml. High density-
lipoprotein cholesterol (HDL-C ) <50 mg/ml in men or <55 mg/dl in women. Patients were
randomly assigned to an open-label therapy with either ezetimibe (10 mg/day) or ERN
(target dose 2,000 mg/day, after an initial dose of 500mg was increased by 500 mg every
other week). The primary end point was change in mean CIMT, analyzed according to a
last observation carried forward method. Change in mean CIMT was obtained with carotid
ultrasound examinations. The product of medication adherence, ERN dosage achieved and
treatment duration between trial participants was calculated to estimate the cumulative
exposure to study drugs as an integrated measure of drug effect.
The methodology used in this study allowed it to be terminated after 60% of subjects
completed the trial. The trial was terminated at that point, after evaluation of the primary
end point data. A total of 363 patients enrolled for the trial. 208 patients completed 14
months of study (n=208). 107 patients had completed 7± 3 months at the moment of trial
termination (n=107). 44 patients left the study. The sample size for this study was therefore

2. 315 patients. For statistical analysis, a 2-sided p value of p≤0.05 was considered
statistically significant.
Results:
Baseline characteristics. All trial patients trial had similar baseline values: Sex (80%
male), hypertensive (87%) age (65 ±11 years), health status, personal of family history of
coronary disease, statin therapy and other medications, body mass index and waist
circumference, blood pressure, and mean and maximal CITM. There was no significant
difference in patients baseline covariates among patients that competed 14 month of study
or those participating for 7± 3 months.
Serum biomarkers at study completion. Baseline and final lipid and biomarker values in
the patients showed significant reductions in baseline LDL-C and triglycerides with both
ezetimibe and ERN. As compared with ERN, patients treated with ezetimibe achieved
significantly lower total cholesterol, LDL-C, and HDL-C, and had higher triglyceride values.
Primary end point. Only treatment with ERN (n=154) resulted significant reduction in
mean CIMT (-0.0102 ± 0.0026 mm, p value change from base line ≤ 0.001) and maximal
CIMT (-0.0124 ± 0.0036 mm, p value change from base line =0.001) compared to baseline.
Ezetimibe (n=161) had no effect in mean (-0.0016 ± 0.0024 mm) or maximal (-0.0005 ±
0.0029 mm) CIMIT statistical values compared to baseline.
Impact of cumulative drug exposure. Increased cumulative drug exposure resulted in
regression of CIMT with ERN, and progression of CIMT with ezetimibe. The subgroup of
ERN-participants treated optimally (best drug adherence at 2,000 mg/day for 14 months),
achieved significant reduction of mean CIMT from baseline (-0.0128 ± 0.0078 mm)
whereas patients treated with ezetimibe experienced progression (0.0067 ± 0.0059 mm).
Discussion. ERN cumulative exposure on CIMT response is consistent with previous
observations of niacin on clinical events and atherosclerosis. However, the inverse
relationship between intensity of ezetimibe exposure and CIMT was unexpected, and
suggests that the pharmacologic effects of ezetimibe extend beyond the inhibition of enteric
cholesterol absorption, and reduction of LDL-C.
Conclusions: Final results from the ARBITER 6-HALTS trial confirm the superiority of ERN
over ezetimibe, for the end point of change in CIMT, and the ability of ERN to induce CIMT
regression. Increased cumulative drug exposure was related to regression of CIMT with
ERN, and progression of CIMT with ezetimibe.
Note: A limitation of this study is the use of CIMT as a surrogate for clinical end points.