R3i Editorial

ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) is the first trial to show that a treatment strategy aimed at raising HDL-C in high-risk statin-treated patients at LDL-C goal (<100 mg/dL or 2.6 mmol/L) produces regression of atherosclerosis compared with an intensive LDL-C lowering strategy.(1) These results are supportive of the residual cardiovascular risk concept per se, of a lipid-related modifiable component to this risk, and of the value of targeting non-LDL lipids to reduce this risk.

In a previous position statement,(2,3) the Residual Risk Reduction Initiative (R³i) has argued for consideration of treatment strategies to address the high level of residual cardiovascular risk due to non-LDL lipids in statin-treated patients. This is supported by initial data from the REALIST (REsiduAl risk Lipids and Standard Therapies) macrovascular survey showing that low HDL-C and/or elevated triglycerides, components of atherogenic dyslipidemia, are strong indicators of residual macrovascular risk.(4) Whether raising HDL-C and/or lowering triglycerides, against a background of statin therapy, reduces this risk is more contentious. Imaging studies in patients treated with niacin plus a statin showed that raising HDL-C was associated with stabilization, or even regression of atherosclerosis, relative to statin alone(.5-7) Indeed, Lee et al. reported in statin-treated patients with coronary heart disease receiving a high-dose niacin (2 g/daily vs. placebo) a significant reduction (p=0.03) of the MRI-measured carotid atherosclerosis.7 In contrast, the ENHANCE study conducted in patients with famililal hypercholesterolemia failed to demonstrate an effect on progression of carotid atherosclerosis of a simvastatin-ezetimibe combination compared with simvastatin alone.(8) However, because the therapeutic effect of ezetimibe is to lower LDL-C, ENHANCE did not test the residual risk hypothesis as regards atherogenic dyslipidemia, raising HDL-C and lowering triglycerides. In the only outcome study to date to test this strategy to raise HDL-C in the context of statin treatment, torcetrapib on top of atorvastatin was associated with significant excess in mortality and cardiovascular events, despite substantial increases in HDL-C., although this was subsequently attributed to off-target adverse effects of torcetrapib,(9) or else to the specific way torcetrapib raises HDL-C by inhibiting cholesterol ester transfer protein.

In ARBITER 6-HALTS, all patients were treated first with a statin, mainly simvastatin or atorvastatin, and achieved at baseline a mean LDL-C concentration of 80 to 84 mg/dL. Then they were randomly assigned to receive treatment with extended-release niacin at a clinically relevant target dose of 2 g daily or ezetimibe at a dose of 10 mg per day. Because niacin lowers LDL-C, the use of ezetimibe in the control group maintained equality in LDL-C levels in both groups during the study at 67-70 mg/dL. This research strategy isolated niacin’s actions to raise HDL-C and lower TG from its effects on LDL-C. After 14 months of treatment, niacin raised HDL-C by about 25% compared to the ezetimibe group and decreased triglycerides by about 20% (median 90 mg/dL). These changes were associated with atherosclerosis regression, assessed by carotid-intima media thickness, after 14 months in the niacin compared to the ezetimibe group which showed no change in IMT. These findings therefore show that raising HDL-C and lowering TG even in statin-treated patients with well-controlled LDL-C provides added benefit to atherosclerosis, consistent with the position taken by the R3i.

We should, however, recognize a number of limitations of these data. Firstly, ARBITER 6-HALTS was an imaging study in a small number of patients (208 completers) that measured changes in carotid intima-media thickness, a surrogate subclinical endpoint for atherosclerosis and cardiovascular events. It does not tell us anything directly about the efficacy of either niacin or ezetimibe, the comparator for preventing cardiovascular events. Secondly, the patients who were enrolled in the study should not be considered good candidates for ezetimibe treatment because their LDL-C levels were already well beneath treatment goal. The use of ezetimibe should be viewed mainly as a means to equalize the LDL-C levels in the two groups to isolate the HDL-raising and TG-lowering effects of niacin. Thirdly, treatment duration was limited to 14 months. In contrast, outcomes studies usually provide follow-up data over several years. Fourthly, the study was terminated prematurely after an interim analysis showed significant thickness regression, relative to the comparator, at both 8 and 14 months. However, stopping rules for the study were not formally pre-specified, as is accepted practice in clinical trials. For a recent example, the JUPITER trial was prematurely terminated after 1.9 years due to 44% reduction in the relative risk of major cardiovascular events in healthy individuals with elevated hsCRP.(10) Whether significant benefit in terms of a surrogate endpoint, rather than clinical outcomes, warrants early termination is certainly controversial and has polarized clinical opinion. On this point, the R3i Trustees would confer with the conclusions of Dr John JP Kastelein, Academic Medical Center, University of Amsterdam, The Netherlands and lead investigator of the ENHANCE trial, who suggested that while the results of ARBITER 6-HALTS are probably correct, they are likely to be overestimated.(11) On a conceptual basis, the ARBITER 6-HALTS design randomized either ezetimibe or niacin as secondary agents to administer a lipid-lowering bitherapy, with a statin, as common denominator in both arms, already yielding target LDL-C at baseline. While using a statin plus ezetimibe is strictly-speaking a combination of two lipid-lowering agents, ezetimibe is essentially a statin enhancer aimed at amplifying LDL-C lowering brought about by the background statin, rather than an autonomous hypolipemic agent with sufficient intrinsic lipid-lowering effect to be used in monotherapy. In a bitherapy scheme, ranking ezetimibe on a par with niacin, a compound with marked effects on two non-LDL components of dyslipidemia associated with post-statin residual risk, may handicap the former compound in a head-to-head prospective trial, the more so that LDL-C was already below goal at baseline.

Despite these limitations, ARBITER 6-HALTS provides encouraging data consistent with the hypothesis that, in patients who have already reached LDL-C target levels, intervening to raise HDL-C and lower triglycerides reverses atherosclerosis and reduces coronary heart disease. It also suggests 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 component of residual cardiovascular risk. However, we still need data from outcomes studies. In this respect we eagerly await the results of key outcomes studies, AIM-HIGH, HPS2-THRIVE, and ACCORD (due very shortly) which are investigating treatments that address atherogenic dyslipidemia (either fenofibrate or niacin), against a background of statin therapy. The first of these, ACCORD, is expected in early 2010.

References

1. Taylor AJ, Villines TC, Stanek E, Devine PJ, Griffen L, Miller M, Weissman NJ, Turco M. Extended-release niacin or ezetimibe and carotid intima-media thickness. New Engl J Med 2009;361. Published on-line November 15, 2009. DOI 10.1056/NEJMoa0907569.
2. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients. Diabetes Vasc Dis Res 2008;5:319-35.
3. Fruchart JC, Sacks FM, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients. Am J Cardiol 2008;102(suppl 10A): 1K-34K.
4. ESC newsletter, 2009.
5. Brown BG, Zhao XQ, Chait A et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
6. Taylor AJ, Sullenberger LE, Lee HJ et al. 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 2004;110:3512-7.
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.
8. Kastelein JJP, Akdim F, Stroes ESG, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43.
9. Barter P, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komadja M, et al. ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. New Eng J Med 2007; 357: 2109-22.
10. Ridker PM, Danielson E, Fonseca FA et al, for the JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reative protein. N Engl J Med 2008;359:2195-207.
11. 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.