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)
Why the study?
The ARBITER 6-HALTS trial was conducted to compare the effects of niacin versus ezetimibe on carotid intima-media thickness in patients with CHD or CHD equivalent on stable statin therapy with low HDL and LDL cholesterol below 100 mg/dl.
Does extended-release niacin reduce mean carotid intima-media thickness compared to ezetimibe in patients with coronary heart disease on stable statin therapy?
Key Points
- To report the final results comparing extended-release niacin against ezetimibe on changes in carotid intima-media thickness in patients with coronary heart disease receiving stable statin therapy.
- In this randomized superiority trial (NCT00397657), 315 patients with coronary heart disease or equivalent on stable statins were randomly assigned to ezetimibe (10 mg/day) or extended-release niacin (target dose 2,000 mg/day).
- Patients had LDL cholesterol <100 mg/dl and HDL cholesterol <50 mg/dl (men) or <55 mg/dl (women); 208 completed 14-month follow-up and 107 were assessed after an average of 7 ± 3 months following early trial termination.
- The primary end point was change in mean carotid intima-media thickness (CIMT) evaluated using last observation carried forward.
- Extended-release niacin (n = 154) significantly reduced mean CIMT by -0.0102 ± 0.0026 mm (p < 0.001) and maximal CIMT by -0.0124 ± 0.0036 mm (p = 0.001), whereas ezetimibe (n = 161) did not reduce mean (-0.0016 ± 0.0024 mm; p = 0.88) or maximal CIMT (-0.0005 ± 0.0029 mm; p = 0.88).
- Between-group comparisons significantly favored niacin over ezetimibe for changes in both mean CIMT (p = 0.016) and maximal CIMT (p = 0.01).
- Greater cumulative drug exposure correlated with regression of CIMT in the niacin group but was associated with progression of CIMT in the ezetimibe group.
Study Design
Type
RCT (n=315)
Randomization
randomly assigned
Structured PICO
Does extended-release niacin reduce mean carotid intima-media thickness compared to ezetimibe in patients with coronary heart disease on stable statin therapy?
P
Population
315 patients with coronary heart disease or CHD equivalent on stable statins with LDL-C <100 mg/dl and low HDL-C, followed for up to 14 months.
I
Intervention
Extended-release niacin (target dose, 2,000 mg/day) added to stable statin treatment
C
Comparator
Ezetimibe (10 mg/day) added to stable statin treatment
O
Outcome
Change in mean carotid intima-media thickness (CIMT)surrogate
Main Result
Absolute Event Rate: -0.0102% vs -0.0016%
p-value: p=0.016
Limitations
- Early trial termination based on pre-specified interim analysis
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“The proper framework of the ARBITER 6-HALTS study is to compare the effectiveness of two drugs. In this regard, the data are clear--niacin is clearly superior to ezetimibe. That's good news for patients, and it's also good news for doctors who need to know how different drugs compare against one another so they can practice evidence-based medicine.”
“If you practice evidence-based medicine in 2009, after high-dose statin therapy, niacin is your number-two drug. The amount of evidence available for niacin, although it's less than for high-dose statins, dwarfs the evidence available for any of the prevention interventions that we currently have available. It certainly dwarfs the evidence available for ezetimibe and fibrates, and we really think that niacin should be the number-two drug for all patients who are taking a statin and that doctors should rarely be using ezetimibe these days.”
SNSteven NissenCardiologist, Cleveland Clinic, Ohio
“Niacin is a 50-year-old drug, and you can buy it over the counter at your local pharmacy. When you have an inexpensive therapy like this--there are issues about being able to tolerate high-dose niacin, but if you get patients to tolerate it--niacin looks to be a better strategy.”
Implication
In patients with coronary heart disease on stable statin therapy, the addition of extended-release niacin induced regression of carotid intima-media thickness and was superior to ezetimibe.
Abstract
OBJECTIVES This report describes the final results of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis) trial. BACKGROUND The ARBITER 6-HALTS trial was terminated early on the basis of a pre-specified interim analysis showing superiority of niacin over ezetimibe on change in carotid intima-media thickness (CIMT). After termination, an additional 107 subjects completed a close-out assessment. METHODS Patients with coronary heart disease (CHD) or CHD equivalent with low-density lipoprotein cholesterol <100 mg/dl and high-density lipoprotein cholesterol <50 mg/dl for men or 55 mg/dl for women while receiving stable statin treatment were randomly assigned to ezetimibe (10 mg/day) or extended-release niacin (target dose, 2,000 mg/day). The primary end point was change in mean CIMT, analyzed according to a last observation carried forward method. The relationships of study medication adherence, dosage, and cumulative exposure (product of adherence, dose, and time) with change in CIMT were explored. RESULTS Results in 315 patients included 208 with 14-month follow-up and 107 after mean treatment of 7 +/- 3 months. Niacin (n = 154) resulted in significant reduction (regression) in mean CIMT (-0.0102 +/- 0.0026 mm; p < 0.001) and maximal CIMT (-0.0124 +/- 0.0036 mm; p = 0.001), whereas ezetimibe (n = 161) did not reduce mean CIMT (-0.0016 +/- 0.0024 mm; p = 0.88) or maximal CIMT (-0.0005 +/- 0.0029 mm; p = 0.88) compared with baseline. There was a significant difference between ezetimibe and niacin treatment groups on mean changes in CIMT, favoring niacin, for both mean CIMT (p = 0.016) and maximal CIMT (p = 0.01). Increased cumulative drug exposure was related to regression of CIMT with niacin, and progression of CIMT with ezetimibe. CONCLUSIONS Niacin induces regression of CIMT and is superior to ezetimibe for patients taking statins. (Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis; NCT00397657).
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Cite This Study
Villines et al. (2010) conducted an RCT in Coronary heart disease (CHD) or CHD equivalent (n=315). Extended-release niacin vs. Ezetimibe (10 mg/day) was evaluated on Change in mean carotid intima-media thickness (CIMT) (p=0.016).