AHA: Niacin to take center stage as it beats ezetimibe in ARBITER 6

Following a frenzied build-up (on Wall Street, at least– not so much in the medical community) the results of ARBITER 6 have now been presented at the AHA and published online in the New England Journal of Medicine. The bottom line: niacin but not ezetimibe caused a significant reduction in CIMT.

Although its HDL raising properties have been known for decades, niacin is about to experience its 15 minutes of fame as an overnight success. Whether its fame and notoriety will last longer will depend on more data than ARBITER 6 can provide.

To back up a bit: the ARBITER 6 investigators, led by Allen Taylor, randomized 363 patients with CHD or a CHD-equivalent already receiving statin therapy and who had LDL levels below 100 mg/dl and low HDL levels (<50 mg/dl for men or 55 mg/dl for women) to receive either extended-release niacin (target dose, 2000 mg/day) or ezetimibe (10mg/day). The trial was stopped early after an interim analysis after 208 patients had completed the trial.

At 14 months, niacin but not ezetimibe caused a highly significant reduction in both mean and maximal carotid intima-media thickness. The investigators also reported a paradoxical finding from a post-hoc analysis in which greater reductions in LDL in the ezetimibe group were associated with increases in CIMT. Further, although the absolute number of events were small, there were more major cardiovascular events in the ezetimibe group than in the niacin group.

Early Termination

Since the announcement that the trial had been stopped early, speculation has been rampant (again, perhaps mostly confined to Wall Street) about the reason. In the NEJM paper the authors write:

On June 4, 2009, an independent data advisory committee evaluated the end-point data without knowledge of the treatment assignments. No formal, a priori stopping boundaries were set for the trial. On the basis of efficacy… the committee unanimously recommended that the trial should be terminated. After termination, final visits were conducted, which resulted in 208 patients having 14-month end-point data.

The NEJM publication is accompanied by two editorials, one by John Kastelein (of ENHANCE fame) and Michiel Bots, and one by Roger Blumenthal and Erin Michos. Both editorials express concerns about the decision to stop the trial. Blumenthal and Michos write that the decision “was unfortunate and may exaggerate any potential benefit of niacin therapy,” while Kastelein and Bots write that the “findings might have been strengthened had the trial continued to completion.”

Clinical implications

The trial authors and the editorialists agree that ARBITER 6 is unable to provide firm guidance for clinical decisions, but each tentatively suggest that niacin is now the preferred second agent when aggressive statin therapy is not enough, and each suggest that ezetimibe moves further down the treatment ladder. The ARBITER investigators point out that despite its LDL lowering effects ezetimibe may have adverse effects on reverse cholesterol transport.

Kastelein and Bots raise the question whether we will ever find out the truth about ezetimibe: In their editorial they write that “the large number of hard clinical end points (>5000) required to achieve sufficient statistical power in IMPROVE-IT makes it uncertain whether the trial will ever reach completion.” CardioBrief received the following response to this statement from IMPROVE-IT PI Robert Harrington: “IMPROVE IT is moving along nicely. Patients being enrolled and events accruing. Trial leadership continues to evaluate trial assumptions based on accumulating aggregated data. DSMB continues to review safety. Not much more to report other than trials studying chronic diseases take time.”

Steven Nissen provided the following commentary to CardioBrief:

Although Arbiter-6 was a small study, it must be interpreted in the context of prior studies. This is the third “strike” for Vytorin. The Enhance Trial showed no benefit despite a large reduction in LDL Cholesterol. The SEAS trial failed the primary endpoint. Now, Arbiter 6 shows not only a lack of benefit compared with niacin for carotid IMT, but also a statistically significant difference in clinical outcomes. Also concerning is the regression analysis showing a paradoxical relationship between LDL lowering in the ezetimibe group and change in IMT.

For any new therapy, it is incumbent upon the drug-maker to demonstrate clinical benefit. For Vytorin, we are still waiting. Furthermore, the ongoing IMPROVE-IT Trial is many years from completion and powered to show an extremely small difference in clinical outcome. It may be too little, too late.

Roger Blumenthal expanded on his editorial for CardioBrief, saying that ARBITER 6 was

…a well done imaginative study that will likely change practice. The Oxford Niacin MRI study and HALTS both show statistically improvements. I think that many more doctors will add niacin as a second agent after a statin and the use of ezetimibe will continue to decline. We tried to make the point that the difference in clinical events at 9 versus 2 may have been more dramatic over time or perhaps it would have evened out. This will go down as a landmark trial in preventive cardiology. In 2 years we will know the real story with the large clinical events trials.

Sanjay Kaul provided the following comment to CardioBrief:

There is very little or new in terms of science in this study. There
are several limitations of the study that preclude drawing any
meaningful inference to impact clinical practice. These include the
small size, short duration, open label design, use of a surrogate
endpoint, incomplete data presentation, and finally the unprecedented
decision to prematurely stop the trial on the basis of a treatment
effect on a surrogate endpoint. All of these should serve to temper
the conclusions of this study. Thus, this study will have little
impact on my practice of prescribing ezetimibe only as a last option
after statins (first-choice therapy) and niacin, fibrates or resins
(second-choice therapy).

In my opinion, the bigger story is that nearly 7 years have passed
since the approval of ezetimibe and information is still lacking
whether this drug will reduce the morbidity and mortality from
cardiovascular disease. Even after the completion of the IMPROVE-IT
trial in the next year or so, it is unlikely that a clearer picture of
the benefit-risk profile of ezetimibe will emerge given the
requirement of a large number of events (perhaps up to 5000) to
achieve adequate statistical power. Who bears responsibility for this
evidence-free vacuum that tends to invite confusion and uncertainty
among patients, physicians, and policy makers? Ideally, the FDA should
only grant provisional approval on the basis of surrogate endpoint (as
in the case of ezetimibe which was approved on the basis of LDL
lowering) conditioned on demonstration of efficacy and safety in
efficiently designed clinical outcomes studies. Such lifecycle
evaluations might provide effective remedies against the current
shortcomings inherent in drug evaluation and approval.



Click here to see all of CardioBrief’s coverage of ARBITER-6



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