Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 82nd Scientific Sessions of the American Heart Association

Orlando, Florida / November 14-18, 2009

ARBITER 6-HALTS in Perspective

A surrogate end point study, ARBITER 6-HALTS, has demonstrated that raising HDL is a viable strategy for preventing growth of atherosclerosis in patients with stable cardiovascular disease (CVD) who already have relatively well-controlled LDL. The ARBITER (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) 6-HALTS (HDL and LDL Treatment Strategies in Atherosclerosis) study compared raising HDL with niacin to further lowering LDL with ezetimibe. The strategy of raising HDL was effective for the carotid intima media thickness (CIMT) end point, but patients entered the study with a median LDL of 2.2 mmol/L at baseline. Study findings suggested that raising HDL might be an important next step toward further controlling atherosclerosis when LDL is already controlled. However, the results offer no change in the importance of reaching LDL goals whether with ezetimibe or any other lipid-lowering strategy. There was substantial concern at the meeting that these results may have been misinterpreted.

“This study provides another piece of evidence to suggest that the addition of niacin to a statin adds benefit, but it does not tell us anything about ezetimibe,” concurred Dr. Lawrence Leiter, Division of Endocrinology and Metabolism, St. Michael’s Hospital, University of Toronto, Ontario. “It should have no affect on current strategies to prevent CVD by lowering LDL. Patients who are not reaching their LDL target on a maximally tolerated statin should receive a second drug such as ezetimibe to reach their targets.”

Study Background

In ARBITER 6-HALTS, which was published online at the same time that it was presented here at the AHA, 363 patients with stable coronary artery disease and a median LDL of 2.2 mmol/L were randomized to extended-release niacin with a target dose of 2000 mg/day or ezetimibe 10 mg/day (Taylor et al. N Engl J Med 2009;361(21):1-10). The primary end point was change from baseline in the mean CIMT after 14 months. The study was designed to determine whether a strategy of raising HDL or further lowering LDL in patients with good LDL control was more efficacious for the surrogate disease end point of growth of atherosclerosis on CIMT.

At an interim analysis when 208 of the 363 patients had completed 14 months of follow-up, an independent data advisory committee recommended halting the study because there was a significant difference between the two groups. Although no boundaries for ending the study were prespecified and there were no safety issues, the senior author of the study, Dr. Allen J. Taylor, Medstar Research Institute, Washington Hospital Center, Washington, DC, explained that the study hypothesis, which predicted greater benefit from raising HDL than further lowering LDL, had been met. When groups were compared at this point, there were highly statistically significant reductions in both mean (P=0.003) and maximal (P=0.001) CIMT relative to baseline in the niacin-treated group. There was no significant increase or decrease in the ezetimibe group.

The early termination of the study, particularly in the absence of any safety concerns, was strongly criticized by several investigators, including the invited discussant at the AHA, Dr. John J.P. Kastelein, Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Although he considered the study to be otherwise well conducted, he cautioned that there are multiple statistically-based reasons to be concerned about studies with an early termination. He also noted that while this study was a good test of the effect of raising HDL on showing change in CIMT, it was not a good test of the effect of change in LDL. Although niacin raised HDL by 18.4% and ezetimibe reduced LDL by 19.2%, LDL was also reduced by 17.6% in the niacin group whereas ezetimibe had no significant effect on HDL. At the end of 14 months, LDL levels were not significantly different in the two groups. Again, there was no placebo group.

Reaching LDL Targets Vital

Several media reports interpreted the results of ARBITER 6-HALTS as a challenge to ezetimibe as a strategy for lowering LDL, but several experts quickly identified this as a fundamental misinterpretation. Although several Canadian specialists expressed interest in the potential clinical significance of benefit of niacin on the surrogate end point of CIMT, most emphasized that the study has no relevance to LDL lowering, which was not different in the two groups. For example, Dr. Jean Grégoire, Department of Medicine, Montreal Heart Institute, Quebec, emphasized that this trial was not of clinical end points and that the results had absolutely no effect on the LDL hypothesis of benefit or the need to reach currently defined targets.

“The new [Canadian] guidelines that were published just a few weeks ago recommend a low LDL,” Dr. Grégoire noted. He added, “Many of our patients who receive treatment with a statin do not succeed in reaching the therapeutic threshold. It is important to remember that the primary targets rest with LDL. As a result [of these low targets], I think that ezetimibe remains an essential tool in the therapeutic arsenal to allow us to reach these targets.”

The official spokesperson for the AHA, Dr. Robert Eckel, Professor of Medicine, University of Colorado, Denver, made the same point. Although he acknowledged that the ARBITER 6-HALTS study was a well-designed assessment of the effect of niacin on CIMT, it did not alter current LDL guidelines or affect strategies to help patients reach the targets identified in guidelines. “I see at this point no reason to be concerned about using ezetimibe as an LDL-lowering therapy as an option for patients requiring further LDL lowering,” Dr. Eckel told delegates.

Clinical Implications

It was widely agreed that the study did provide compelling evidence that raising HDL with niacin provides greater protection against growth of atherosclerosis as revealed by CIMT. However, several experts, including Dr. Grégoire, described CIMT as an intriguing surrogate for understanding the pathophysiology of atherosclerosis but not one that can be used to alter clinical practice. He noted that not all studies that have associated treatments with clinical benefits have provided protection against atherosclerosis as measured by CIMT. There are multiple mechanisms likely to be important to reducing risk of events, including stabilizing plaques to prevent the ruptures that provoke thrombi. “It is interesting to use the IMT [to explore mechanisms], but it is very far from being as useful as a study of events. I do not think one can extrapolate the changes in IMT for predicting clinical results of an event trial,” Dr. Grégoire suggested.

Offering a similar perspective, Dr. Leiter cited studies associating both rosiglitazone and estrogen with reductions in CIMT although both have subsequently been associated with increased CV risk. Conversely, the benefit of LDL lowering has been highly consistent across statins as well as non-statin therapies. Dr. Leiter cited a meta-analysis of non-statin therapies in which the correlation between reductions in LDL and reductions in CV events was consistent regardless of how the LDL reduction was achieved. “The ARBITER study was interesting, but it does not tell us anything about ezetimibe,” remarked Dr. Leiter, emphasizing the lack of a placebo arm that might have associated ezetimibe with protection against progression of atherosclerosis. He suggested that outcome studies are needed for any strategy, but the LDL hypothesis remains well established with consistent results across a large number of multinational studies conducted over the past 15 years.

From a practical standpoint, one of the obstacles with raising HDL using niacin, which was again observed in the ARBITER 6-HALTS study, was tolerability. Fully 25% of patients were never able to achieve the target dose and 15% of the niacin patients dropped out of the study vs. 9% in the ezetimibe group. The main problem with niacin in this and other studies was flushing even though the extended-release formulation was used. Adherence rates among those who stayed in the study was highly statistically significant, favouring ezetimibe (95% vs. 88%; P<0.001).

Summary

In a study with data of 208 patients with coronary heart disease and relatively well-controlled LDL on a statin, adding niacin to increase HDL produced a reduction in atherosclerosis as measured with CIMT, while a strategy of further lowering LDL with ezetimibe did not produce regression (although no progression was observed). The study provides support for the concept of treating HDL once LDL is well controlled but does not challenge the importance of reaching LDL targets with appropriate therapy, including ezetimibe. Clinical trials to confirm the hypothesis that raising HDL provides protection against clinical events, as predicted by this study, are needed.

Note: This report is based on the 82nd Scientific Sessions of the American Heart Association Late-breaking Clinical Trials II presentation on Monday, November 16, 2009, Orange County Convention Center, Orlando, Florida, West Hall D2, 11:07 a.m.