Originally published in MedPage Today

by Peggy Peck, MedPage Today Executive Editor

Boosting HDL cholesterol with extended-release niacin (Niaspan) is a more effective way of slowing atherosclerosis in high-risk patients on long-term statin therapy than seeking additional LDL cholesterol reductions by adding ezetimibe (Zetia), researchers here reported.

Compared with ezetimibe, 2 grams of niacin led to significant reductions in both the mean and maximal carotid intima-media thickness (CIMT) (P≤0.001 for all comparisons), Allen J. Taylor, MD, of the Walter Reed Army Medical Center, told MedPage Today.

Taylor was principal investigator of the ARBITER 6-HALTS trial, whose results were reported today at the American Heart Association meeting and simultaneously published online in the New England Journal of Medicine.

Although ezetimibe significantly reduced LDL by 19.2%, to an average of 66 mg/dL, the “greater reductions in LDL cholesterol level in association with ezetimibe were significantly associated with an increase in carotid intima-media thickness,” according to a post hoc analysis conducted by Taylor and colleagues.

“Niacin had a superior effect on the artery wall,” he said, “so the take home message is clear: niacin should be the choice when considering an add-on therapy.”

While that was the answer to the clinical question posed by the trial, the finding that created the greatest buzz at the AHA meeting came from analysis of a secondary endpoint.

The rate of major adverse cardiac events (myocardial infarction, revascularizaton, cardiovascular death, and hospitalizations for acute coronary syndrome) was 1% in the niacin arm versus 5% in the ezetimibe arm (P=0.04).

Although statistically significant, that difference represents just seven patients, nine patients in the ezetimibe arm versus two in the niacin arm. Moreover, since the trial was not designed to investigate MACE, the result should be considered hypothesis-generating only, researchers said.

Also, the trial itself was small — just 208 patients had completed 14 months when it was terminated because “the clinical question was answered and having answered it, the trial lost clinical equipose,” Taylor said.

That early termination caused some critics to question the impact of the results.

Roger S. Blumenthal, MD, of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, said that since the trial was originally designed as a 360 patient study, continuing the study until all patients had completed the trial would have provided more compelling evidence.

“The absolute difference might have gotten smaller or it might have gotten bigger,” Blumenthal told MedPage Today.

He made that same point in an editorial that was published along with the study.

The premature termination, as he and Hopkins colleague Erin D. Michos, MD, MHS, wrote, “was unfortunate and may exaggerate the potential benefit of niacin therapy.”

But, Blumenthal agreed that Taylor made a valid point about the lack of clinical equipose and said the investigators clearly had a right to terminate the study.

Arguably the most interesting comments about ARBITER 6-HALTS came from John J.P. Kastelein, MD, PhD, who co-authored a second editorial in NEJM.

Kastelein was lead author of the ENHANCE trial, another trial that used CIMT to compare statin therapy alone to the combination of ezetimibe and simvastatin marketed as Vytorin.

That trial was also negative. and when it was reported at the American College of Cardiology and simultaneously published in NEJM, Taylor wrote an editorial suggesting that ezetimibe was being overused.

In his turn as editorialist, Kastelein agreed with the ARBITER 6-HALTS investigators, writing 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 patient at high cardiovascular risk.”

W. Douglas Weaver, MD, immediate past president of the American College of Cardiology, called Niacin “an effective, but underutilized drug.”

“This study shows that until the ongoing large study of [ezetimibe] is completed, the clinical effectiveness of [ezetimibe] is unknown and the drug should be reserved for those patients who cannot achieve suitable cholesterol levels with statins alone or with a combination of statins and niacin,” he added.

“For patients who cannot reach their cholesterol goals with statin therapy alone, this study, though small, shows that niacin is a much better choice than ezetimibe as an add-on medication. Until there is an outcomes trial, ezetimibe and Vytorin should be drugs of last resort. This study further reinforces our recommendations that statins should always be the first-line treatment,” Weaver said.

Anthony DeMaria, MD, Editor-in-Chief of the Journal of the American College of Cardiology, noted that “this is a small trial with a small number of cardiovascular events.”

“This trial doesn’t quite put the nail in the coffin for ezetimibe, but it pushes it way down on the list of medications for cholesterol-lowering therapy,” he said.

Jim Stein, MD, of the Medical College of Wisconsin, had even stronger advice for colleagues:

“Doctors need to stop using so much ezetimibe. Using this drug is not practicing evidence-based medicine. It is taking a path of least resistance — the easy way out of getting numbers to targets. But we don’t treat numbers, we treat patients, and are obligated to use drugs that are proven in clinical trials to reduce things they care about — heart attacks, strokes, and death — and to do so safely.”

Taylor carefully avoided making statements about the efficacy of ezetimibe, although he acknowledged that a number of studies have questioned it, and he has written editorials doing the same.

However, in the NEJM paper, there is a lengthy discussion of the mechanism of ezetimibe, including the thesis that ezetimibe can inhibit cholesterol-transport proteins.

“We hypothesize that the seemingly paradoxical association of greater ezetimibe-induced reduction of LDL cholesterol level with a greater increase in carotid intima-media thickness is biologically plausible if it is associated with the unintended disruption of reverse cholesterol transport,” they wrote.

Ray Gibbons, professor of medicine at the Mayo Clinic in Rochester, pointed out that the patients in the ARBITER 6-HALTS study were already quite well-managed, as most had LDLs of less 100 mg/dL, so they could hardly be considered typical.

“In my practice, I follow previous outcomes studies (and AHA position), i.e., niacin is the preferred second agent if statins at maximum tolerated dose do not get patients to target,” Gibbons said.

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