Correspondence University of Washington, Medical Center, 1959 N.E. Pacific Street, Campus Box 356422, Seattle, WA 98195, USA

Email bgbrown@u.washington.edu

Original article

Taylor AJ et al. (2004) Arterial Biology for the Investigation of the Treatment Effects of Reducing cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 110: 3512–3517   PubMed

Synopsis

Background

Low HDL-cholesterol concentrations can be successfully raised by niacin. A low HDL-cholesterol level is recognized as a coronary risk factor and increases the risk of unfavorable events related to coronary atherosclerosis. Unlike for LDL cholesterol, the National Cholesterol Education Program guidelines do not provide target levels for HDL-cholesterol concentration. Few studies have investigated the effect of niacin on coronary events, alone or in combination with statin therapy.

Objectives

To explore the effect of niacin on carotid intima–media thickness (CIMT), and to find out whether extended-release niacin therapy provides added cardiovascular protection to patients receiving statin monotherapy for coronary artery disease.

Design

The Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 trial was a US-based, randomized, placebo-controlled, double-blind study carried out from December 2001 to May 2003. Patients aged over 30 years old were eligible for the study if they had coronary vascular disease, were receiving statin therapy and had HDL-cholesterol levels below 1.7 mM/l (45 mg/dl) and LDL-cholesterol levels under 3.4 mM/l (130 mg/dl). Men and women were excluded if their liver-associated enzyme levels were 3 times the upper normal limit, if they had previous liver disease or were intolerant to niacin.

Intervention

Eligible patients were randomly assigned 500 mg extended-release niacin (Niaspan®, Kos Pharmaceuticals) daily or placebo, both to be taken at night. After 30 days, niacin dose was raised to 1000 mg daily and maintained at this dose for 1 year. Each patient's CIMT was assessed by linear-array 8 MHz probe ultrasonography at baseline and at 1 year. Analysis of CIMT images was masked.

Outcome measures

The main endpoint was change in CIMT over 1 year. An increase in liver-associated enzymes, changes in serum lipid levels and admission to hospital for stroke, arterial revascularization, acute coronary syndrome or sudden cardiac death, among others, were some of the secondary endpoints.

Results

Of the 167 patients on baseline statin treatment, 87 patients were assigned additional niacin therapy and 80 were assigned placebo. In total, 149 patients (89.2%) were reassessed at 1 year (study end). Treatment with statin and niacin significantly increased HDL-cholesterol levels by 21%, from 1.0 0.2 mM/l (39 7 mg/dl) to 1.2 0.4 mM/l (47 16 mg/dl), when compared with statin and placebo (P = 0.002). Although not significant, patients treated with statin and placebo had a higher average increase in CIMT than the statin and niacin-treated patients (0.044 0.100 mm vs 0.014 0.104 mm, P = 0.08). Importantly, the rise in average CIMT was significant for statin and placebo-treated patients but not for patients receiving niacin (0.044 0.100 mm, P <0.001 and 0.014 0.104 mm, P = 0.23, respectively).

Conclusion

Extended-release niacin slowed the development of atherosclerosis in adults with coronary artery disease, independently from statin therapy.

Commentary

In 1991, the Framingham Study analysis told us that "roughly speaking, a 1% increase in LDL cholesterol or a 1% decrease in HDL cholesterol each add independently about 1% to the population risk".¹ This statement implied, but did not prove, that lowering LDL cholesterol or raising HDL cholesterol could likewise diminish clinical complications of atherosclerosis. This epidemiologic prediction has been proved true for LDL cholesterol. Landmark statin trials have demonstrated that a 25–35% reduction in LDL cholesterol results in a roughly 25–35% reduction in major cardiovascular events and can slow, but not halt, the progression of coronary artery stenosis. Unfortunately, our understanding of the benefits of raising HDL cholesterol is not as complete. The ARBITER 2 findings, together with other study results, however, are encouraging. Certain HDL-cholesterol-raising drugs favorably impact atherosclerosis and patients' clinical risk, independently of LDL-cholesterol reduction. This raises the hope that the combination of lowering LDL-cholesterol levels and raising HDL-cholesterol levels will reduce a patient's lipid-attributable risk by 60–80%. If confirmed, this will introduce a change in the practice of cardiovascular medicine.

The ARBITER 2 findings are consistent with this inference and with other trial results. The Pravastatin, Lipids, and Atherosclerosis in the Carotid arteries trial (PLAC-II)² demonstrated that progression of carotid atherosclerosis was slowed but not halted by statin therapy. The Coronary Drug Project³ showed that niacin reduced the risk of nonfatal myocardial infarction by 27% and stroke by 26%. The addition of niacin to statin therapy produced highly favorable incremental effects on LDL cholesterol and HDL cholesterol, triglyceride and lipoprotein-a levels,^{4, 5} which are all components of dyslipidemia that contribute to a patient's risk. In the HDL–Atherosclerosis Treatment Study (HATS),⁵ a 26% increase in HDL cholesterol and a 42% reduction in LDL cholesterol using niacin and simvastatin, respectively, resulted in regression of coronary stenosis and a 60% reduction in a composite of major clinical events, relative to placebo.

Many physicians rely on practice guidelines. Unless the guidelines are altered in response to the collective evidence, the results of Taylor et al.'s study, and others, will not have a major immediate effect on practice. Some physicians, however, are students of this emerging understanding, are aware of guideline changes regarding HDL cholesterol and triglyceride levels, and are in the vanguard of this potential change in treatment strategy.

In any study examining a surrogate clinical endpoint in a small population, such as CIMT in Taylor and colleagues' paper, the clinical relevance of the findings will be questioned. Despite pathologic and trial evidence showing that measurement of the progression of atherosclerosis is a strong predictor of clinical events, skepticism of such studies persists. Greater confidence is given to studies addressing the impact of therapy on actual clinical events. A specific criticism of the ARBITER 2 study is the borderline significance of the superiority of extended-release niacin added to statin therapy, compared with statin therapy alone in patients already at LDL-cholesterol target (P = 0.08). The extended-release niacin dose of 1000 mg daily is relatively small, and the 1-year study duration is short. A larger dose and a longer follow-up would predictably strengthen a future study's conclusions.

Now is the time for a landmark niacin–statin versus statin monotherapy trial in several thousand patients to confirm, or reject, the conclusions of the small but compelling early clinical trials.

Acknowledgments

The synopsis was written by Hannah Camm, Associate Editor, Nature Clinical Practice.

References

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Subject areas under which this article appears: Therapy | Vascular disease