$4.6 B/Yr. Later, Zetia/Vytorin Shown Inferior

November 16, 2009

In a study presented yesterday at the American Heart Association conference in Orlando, extended-release niacin (Niaspan) beat ezetimibe (Zetia, a component of Vytorin) in reducing atherosclerosis in high risk patients. Niacin resulted in a significant reduction in thickness of the carotid artery (IMT) while ezetimibe resulted in no change in IMT over the course of the trial.

Niacin raises HDL (“good”) cholesterol and lowers LDL (“bad”) cholesterol, among other effects, while ezetimibe lowers LDL. The New York Times reports this morning that Zetia both alone and in the combination pill Vytorin racked up $4.6 billion in sales last year.

The results of the study, called ARBITER 6-HALTS, have been keenly anticipated because many doctors have been unsure what drug to use as a secondary treatment for patients whose risk is not sufficiently controlled with a statin. The patients in the trial had known vascular disease or a “coronary risk equivalent” such as diabetes, a risk of developing heart disease over the next 10 years of 20 percent or more, or evidence of extensive atherosclerosis as measured by a coronary calcium scan (a type of CT scan). In addition, the participants were required to be on a statin, to have LDL under 100 mg at the beginning of the study, and to have an HDL (“good”) cholesterol level of under 50 mg for men or 55 mg for women. 363 patients were originally enrolled in the trial, but the trial was stopped early in June 2009 by the independent data advisory committee based on differences between the two arms, resulting in 208 patients completing the study.

As discussed previously on Gooznews (see here, here, and here), ezetimibe was approved by the FDA based on its ability to lower LDL but has not yet been shown to prevent heart attacks and strokes. In the ENHANCE trial, reported last year, ezetimibe had no effect on atherosclerosis in patients with genetic high LDL, with the group that received both a statin and ezetimibe achieving the same results as the group that received a statin alone. In the SEAS trial, in patients with aortic stenosis, ezetimibe combined with a statin achieved a 60 percent reduction in LDL but only a 22 percent reduction in heart attacks and other ischemic events as compared to placebo — no more than would have been expected from the statin alone. Thus, although ARBITER was a small trial and was primarily designed to measure a surrogate endpoint (IMT), the results reinforce the already significant doubts about ezetimibe’s effectiveness.

Unexpectedly, there was a significantly higher number of cardiovascular events in the ezetimibe group (9 out of 165 patients (5%)) than in the niacin group (2 out of 160 patients (1%)) (p=0.04). In addition, there were more deaths from any cause in the ezetimibe group (7) than in the niacin group (1). Although these numbers are too small to draw any definitive conclusions, many people will find them far from reassuring, especially in the absence of any evidence that ezetimibe provides any benefit.

In a post hoc analysis, the investigators explored whether there was a relationship between the patients’ LDL levels achieved during the trial and the change in their IMT. Paradoxically, in the ezetimibe group, greater reductions in LDL were associated with an increase in IMT. No such relationship was observed in the niacin group. The researchers hypothesize that ezetimibe’s LDL-lowering may be accompanied by other effects, such as a disruption of the functioning of HDL, that cancel out the effects of LDL-lowering. Post hoc analyses are sensitive to bias, so this finding can only be considered “hypothesis-generating” and would need to be confirmed in other studies.

So where does ARBITER 6 leave us? The bottom line is that this comparative effectiveness trial showed that niacin was significantly more effective than ezetimibe for preventing or decreasing atherosclerosis in patients already on a statin. In an accompanying editorial, John Kastelein, the principal investigator in ENHANCE who receives financial support from Merck, and colleague Michiel Bots, who has financial ties to AstraZeneca, commented that despite certain limitations of the trial, “the primary results are likely to be correct although the magnitude of the difference between the treatment arms may be overestimated” due to the trial’s early termination.

They conclude that “the results available to date provide support for the concept that the use of statins to reduce LDL cholesterol to target levels with the subsequent addition of a drug to raise HDL cholesterol levels (niacin), rather than a drug to lower LDL cholesterol levels (ezetimibe), is a more effective treatment for patients at high cardiovascular risk.” They note that two clinical end point studies — AIM-HIGH (NCT00120289) and HPS2-THRIVE (NCT00461630) will eventually provide further information on whether adding niacin to a statin reduces cardiovascular events.

— Marilyn Mann

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