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15 November 2009
Raising HDL-C and lowering triglycerides further to intensive LDL-C lowering in patients at LDL-C goal. Findings and issues raised by ARBITER 6-HALTS

In high-risk statin-treated patients at LDL-C goal, raising HDL-C and lowering triglycerides with extended-release niacin led to regression of atherosclerosis over 14 months. There was no change in atherosclerosis in a bitherapy arm using ezetimibe to further lower LDL-C below target.

Taylor AJ, Villines TC, Stanek E, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M.
Summary
Comments & References
STUDY SUMMARY
Methods

This study tested two combinations of lipid-modifying agents in high-risk statin-treated patients at LDL-C goal (<100 mg/dL or 2.6 mmol/L):
1. Raising HDL-C and lowering TG with extended-release (ER) niacin (target dose 2 g/day)
2. Further lowering of LDL-C levels with ezetimibe (10 mg/day), a cholesterol absorption inhibitor

The primary objective of ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) was to directly compare the effects of each treatment, added to background statin therapy, on carotid intima-media thickness (IMT), a measure of atherosclerosis used as surrogate endpoint for cardiovascular events. The duration of treatment was 14 months.

Patients who participated in the ARBITER 6-HALTS trial were considered at high risk due to at least one of the following:

  • Known coronary heart disease (CHD) or CHD risk equivalents (36% had diabetes)
  • 10-year global cardiovascular risk ≥20% (Framingham risk score)
  • Coronary calcium score >200 in women or >400 in men

All patients had been previously treated with a statin for at least 3 months (46% with simvastatin and 49% with atorvastatin, average dose 42 ±25 mg/day). Patients at baseline had average HDL-C levels (<50 mg/dL [1.3 mmol/L] in men and <55 mg/dL [1.4 mmol/L] in women).

The primary endpoint was the change from baseline in mean carotid IMT measured by carotid ultrasonography after 14 months. Carotid IMT is a validated measure of atherosclerosis and surrogate cardiovascular endpoint. Secondary endpoints were:

  • Change in lipids (LDL-C, HDL-C and triglycerides) Major adverse cardiovascular events (MACE, a composite of myocardial infarction, myocardial revascularization, hospitalization for acute coronary syndrome, or coronary heart disease (CHD) death)
  • Discontinuation due to adverse effects
  • Health-related quality of life.
Main results

The study was terminated 4 months early on the recommendation of an advisory group on the basis of efficacy, according to an interim analysis of carotid IMT, from 8- and 14-month data. At this time 208 (of 363 enrolled) patients had completed the study. MACE data were evaluated in all enrolled patients.


Key findings are summarised in Table 1.

Table 1. Key endpoints at 14 months


ER niacin (n=97)

Ezetimibe (n=111)

Change in carotid IMT, mm

-0.0142,

-0.0007


p=0.003*

Lipids on-treatment mean concentrations



HDL-C (mg/dL)

49.9

40.5


p<0.001*

LDL-C (mg/dL)

70.5

66.1


p=0.12*

Triglycerides (mg/dL)

90

113


p<0.018*

MACE, % (n) of patients**

1.2% (2)

5.5% (9)


p=0.04*

* vs. ezetimibe

** in all subjects randomized to either ER niacin or ezetimibe

COMMENT

ARBITER 6-HALTS is the first direct comparison of two combinations of lipid-modifying agents aimed at reducing the carotid intima-media thickness (IMT) in high-risk statin-treated patients who have already reached the LDL-C goals defined by current guidelines, i.e. <100 mg/dL. In fact, the mean LDL-C, about 80 mg/dL, was well below this goal. The trial design was successful in isolating the effect of niacin to increase HDL-C and lower TG from its effect on lowering LDL. This was accomplished by using ezetimibe in the control group to approximately equalize the LDL-C levels in both groups during the trial to about 70 mg/dL.

  • The therapeutic strategy used in ARBITER 6-HALTS is based on the fact that niacin raises HDL-C and lowers TG, both powerful risk factors for cardiovascular events even in patients treated with statins and with low levels of LDL-C. Statin therapy is relatively ineffective at increasing low HDL-C levels.

  • Use of ezetimibe, with a sole LDLC--lowering action, produced LDL-C levels in the control group that were similar to those in the niacin group. This was necessary because niacin also lowers LDL-C. To test the hypothesis that treating low HDL-C is beneficial, it was important to factor out LDL-C.

  • The results also suggest that in patients who have especially well-controlled LDL-C, raising HDL-C and lowering triglycerides may be preferable to further LDL-C lowering to reduce the modifiable, lipid-related component of residual cardiovascular risk.


ARBITER 6-HALTS is not a clinical outcome trial. Instead, it explores the efficacy of the two strategies on a surrogate marker, carotid intima-media thickness (IMT), a classical indicator of atherosclerosis.

It must be noted that a simvastatin-ezetimibe combination compared to simvastatin monotherapy in the ENHANCE (1) trial failed to reduce a similar primary endpoint (carotid IMT) despite significant lowering of LDL-C and of the inflammatory marker CRP. However, ENHANCE was conducted in patients with familial hypercholesterolemia, a population known to have highly elevated LDL-C levels and thus much different from that of ARBITER 6-HALTS.

The results of ARBITER 6-HALTS show that raising HDL-C and lowering TG produces regression of atherosclerosis, as assessed by carotid IMT. By comparison, there was no significant change in atherosclerosis with further lowering of LDL-C with ezetimibe.

In an accompanying editorial in the New England Journal of Medicine (2) Dr JJP Kastelein, Academic Medical Center, University of Amsterdam, The Netherlands raised concerns relating to premature termination of the study, given that it was a small imaging trial in a small number of patients, as well as the limited duration of follow-up. Similarly, Drs R Blumenthal and E Michos, Johns Hopkins University, Baltimore, USA, in a second editorial in the journal (3), queried the need to terminate the study early. They argued that a trial should only be prematurely terminated due to futility, an unacceptable safety profile or evidence of a larger treatment effect where the ethical imperative is to protect the study subjects, and considered that none of these criteria applied to ARBITER 6-HALTS. In addition, reduction of the carotid IMT is not necessarily associated with a reduction of the risk of CVD events. Despite these reservations, Dr Kastelein concluded that the primary results of ARBITER 6-HALTS are likely to be correct although the magnitude of the difference may be overestimated. Furthermore, he argued that while the rationale for using niacin was to raise HDL-C levels, the regression in atherosclerosis observed in ARBITER 6-HALTS could not be definitively ascribed to effects on HDL-C, given evidence of benefit on triglycerides and LDL-C. He added that niacin is also known to lower the atherogenic lipoprotein Lp(a) (4), as well as high-sensitivity C-reactive protein (5).

 

Relevance for the residual cardiovascular hypothesis

The findings of ARBITER 6-HALTS are relevant for the residual risk hypothesis for a number of reasons.

The study confirms that residual cardiovascular risk is real. Ezetimibe combined with statin therapy lowered LDL-C beyond recommended levels in high-risk statin-treated patients, but did not significantly reduce atherosclerosis. ER niacin associated with statin therapy significantly raised HDL-C and produced regression of atherosclerosis. The magnitude of the reduction in carotid IMT was clinically meaningful and compared with that reported for statin therapy (6). The ARBITER 6-HALTS findings were also consistent with a recent magnetic resonance imaging study that showed that in statin-treated patients with low plasma levels of HDL-C and clinical evidence of atherosclerotic disease, treatment with niacin reduced carotid atherosclerosis within 12 months relative to placebo (7). Together these findings support the residual risk hypothesis per se, as well as the concept that there exists a lipid-related modifiable component of it, therefore strengthening the argument for intervention against non-LDL lipids – (HDL-C and/or triglycerides) – to address the unacceptably high risk of cardiovascular events in statin-treated patients.

Care should be taken when interpreting the ezetimibe findings. Evidence that ezetimibe did not change atherosclerosis over the 14-month study should not be interpreted as intensive LDL-C lowering provides no clinical benefit. In the absence of a control group with statin alone, the lack of CIMT progression in the ezetimibe group may also hint to stabilization, the natural history of many subclinical atherosclerotic lesions being an increase over time. ARBITER 6-HALTS is an imaging study in a small number of patients. While carotid IMT measurement was highly reproducible, it was also a surrogate endpoint. The reported significant difference in MACE was also based on a small number of events in a limited number of patients. Clearly the results of clinical outcomes studies aimed at addressing atherogenic dyslipidemia - ACCORD, AIM-HIGH and HPS2-THRIVE - as well IMPROVE-IT with ezetimibe, are needed to evaluate the relative clinical benefits of these treatment strategies.


References
  1. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
  2. Kastelein JJP, Bots ML. Statin therapy with ezetimibe or niacin in high-risk patients. New England J Med 2009;361: Published on-line on 15 November. DOI: 10.1056/NEJMe090884.
  3. Blumenthal RS, Michos ED. The HALTS trials – halting atherosclerosis or halted too early? N Engl J Med 2009;361:2178-80.
  4. Guyton JR. Extended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother 2004;5(6);.
  5. Prasad K. C-reactive protein (CRP) lowering agents. Cardiovas Drug Rev 2006;24:33-50.
  6. Yania H, Yoshida H, Tomono Y, Tada N. Atherosclerosis imaging in statin intervention trials. QJM 2007;100:253-62.
  7. Lee JMS, Robson MD, Yu L-M et al. Effects of high-dose modified-release nicotinic acid on atherosclerosis and vascular function. J Am Coll Cardiol 2009;54:1787-94.