Analysis of ARBITER 6-HALTS: HDL Forum Editor, Professor Philip Barter

ARBITER 6-HALTS showed that raising high-density lipoprotein (HDL) cholesterol with niacin produces significant regression of atherosclerosis, as assessed by carotid intima-media thickness, in high-risk statin-treated patients at LDL cholesterol goal. In contrast, there was no change in atherosclerosis with further lowering of LDL cholesterol with ezetimibe. The results of ARBITER 6-HALTS were presented at the American Heart Association Scientific Sessions, Orlando, Florida and published simultaneously in the New England Journal of Medicine. HDL Forum Editor Professor Philip Barter reviews and analyses the trial.

 Taylor AJ, Villines TC, Stanek EJ et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med. Published on-line November 15, 2009. DOI 10.1056/NEJMoa0907569.

 Background to ARBITER 6-HALTS

Overwhelming evidence supports lowering plasma levels of LDL cholesterol to reduce cardiovascular risk (1). Before ARBITER 6-HALTS, however, there was only limited evidence to support the concept that raising HDL cholesterol levels is beneficial. This is despite evidence from population studies showing that a low level of HDL cholesterol is as powerful a predictor of cardiovascular events as a high level of LDL cholesterol (2). Additionally, while the use of ezetimibe combined with a statin reduces LDL cholesterol, data on the clinical value of this strategy are lacking. This was the background to ARBITER 6-HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies).

 ARBITER 6-HALTS planned to enrol 400 patients on long-term statin therapy at high risk of heart disease, with LDL cholesterol levels <100 mg/dL and HDL cholesterol levels <50 mg/dL for men and <55 mg/dL for women. Patients were randomly assigned to adjunctive treatment with extended-release niacin (target dose 2 g daily) or ezetimibe (10 mg daily). The primary study endpoint was the between-group difference in the change from baseline in carotid intima-media thickness, a surrogate cardiovascular endpoint, at 14 months (3).

 ARBITER 6-HALTS: Results

ARBITER-6-HALTS was stopped by the independent steering committee in June 2009 based on results of a prespecified, blinded interim analysis (4).

 Data from 208 patients with 14-month endpoint data were reported; 97 were treated with niacin plus statin and 111 were treated with ezetimibe plus statin. Baseline characteristics of the two groups were similar. Overall, 80% of patients were male, mean age was 65 years, and all patients had coronary heart disease (CHD) or CHD risk equivalents (diabetes). All patients were on a statin, predominantly simvastatin or atorvastatin (mean statin dose 42 ±25 mg for 6 ± 5 years).

 At 14 months, treatment with niacin had raised HDL cholesterol by 18.4% (mean 50 mg/dL), as well as significantly lowering LDL cholesterol and triglycerides. Lowering of LDL cholesterol was similar with ezetimibe (reduction by 19.2%, mean 66 mg/dL) or niacin (reduction by 12.4%, mean 70 mg/dL) (Table 1).

 Treatment with niacin led to significant reduction in the primary endpoint, mean carotid intima-media thickness at both 8 and 14 months (p=0.001 at each time point), as well as significant reduction between 8 and 14 months (p=0.02). In contrast, no significant changes in carotid intima-media thickness were observed in patients treated with ezetimibe. The change from baseline to 14 months in the primary endpoint was significantly different between the niacin and ezetimibe groups (p=0.003) (Table 2). Although not powered for clinical outcomes, the incidence of major cardiovascular events was also significantly lower in the niacin group than the ezetimibe group, 1% (2/160) vs. 5% (9/165), p=0.04.

 

In an accompanying editorial in the New England Journal of Medicine, Professor JJP Kastelein, Professor of Medicine, Academic Medical Center of the University of Amsterdam, The Netherlands indicated that the results of ARBITER 6-HALTS provide support for the concept that raising HDL cholesterol levels (with niacin), rather than further lowering LDL cholesterol levels (with ezetimibe) is a more effective treatment for high-risk statin-treated patients at target LDL cholesterol levels.  Despite the limitations of the trial, relating to its premature termination, the small number of patients studied and the limited duration of follow-up, he concluded that the primary results are likely to be correct although the magnitude of the difference may be overestimated.

 Kastelein JJP, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. New England J Med 2009; Published on-line on 15 November. DOI: 10.1056/NEJMe090884.

 Analysis of ARBITER 6-HALTS

 In his analysis of the trial, HDL Forum Editor Professor Philip Barter, Professor of Medicine, University of Sydney and Director of the Heart Research Institute, Sydney, Australia commented that ARBITER 6-HALTS is an interesting study that adds further evidence to the suggestion that niacin is a very effective drug in reducing atherosclerosis. ‘The results are extremely good news for niacin and for the HDL cholesterol raising hypothesis.’

 ARBITER 6-HALTS also adds to clinical confidence in using niacin, given that there were no serious side effects and treatment was reasonably well tolerated. This is especially relevant for the newer niacin formulations.

 However, these results do need to be placed in context. ARBITER 6-HALTS is a surrogate endpoint study which does not provide any information about the clinical efficacy of either niacin or ezetimibe. The fact that ezetimibe did not significantly change carotid intima-media thickness may mean that atherosclerosis regression requires HDL cholesterol raising, but this may have nothing to do with clinical events. It is a gross over-interpretation of the data to say that these results are also an indictment of ezetimibe.

 ARBITER 6-HALTS provides a really positive message for niacin and for the concept of HDL cholesterol raising. Clearly we need to wait for the results of ongoing clinical outcomes studies, AIM-HIGH and HPS2-THRIVE (for niacin) and IMPROVE-IT (for ezetimibe) to address the issue of clinical efficacy.

 References

1. Baigent C, Keech A, Kearney PM, et al. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet 2005; 366: 1267–78.

2. Gordon DJ, Probstfield JL, Garrison RJ, et al. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989; 79:8-15.

3. Devine PJ, Turco MA, Taylor AJ. Design and rationale of the ARBITER 6 Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol)-6-HDL and LDL Treatment Strategies in Atherosclerosis (HALTS). Cardiovasc Drugs Ther 2007;21:221-5.

4. Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis. http://clinicaltrials.gov/ct2/show/NCT00397657.


Download Attachment