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

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.