Controversial Ezetimibe Trial's Completion Expected in June 2013

April 01, 2010

April 1, 2010 (Durham, North Carolina) — The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) study, testing the controversial cholesterol-lowering drug ezetimibe (Vytorin, Merck/Schering-Plough Pharmaceuticals) added to statin therapy, is expected to be completed in June 2013 [1].

The announcement of the anticipated completion date is based on statistical modeling that allows investigators to track enrolment rates, blinded aggregate event rates, treatment discontinuation rates, and other variables, and is intended to shed light on a study that some experts believed might never be completed.

"There has been a great deal of speculation about when the trial will end," Dr Robert Harrington (Duke University, Durham, NC), one of the IMPROVE-IT investigators, told heartwire . "We take an educated guess at the beginning of a trial, using a lot of assumptions, as to when we'll complete enrolment and when we think we'll accumulate the required events. . . .  The models we use suggest, based on all the things we're observing, that the trial will end in 2013, and as the trial continues to go on for the next year or two, we'll continue to update those models."

We think being pretty certain about the effect of ezetimibe is important.

In a recent editorial accompanying the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6: HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) study, Drs John Kastelein (Academic Medical Center, Amsterdam, the Netherlands) and Michel Bots (University Medical Center, Utrecht, the Netherlands) raised concerns about whether IMPROVE-IT would ever reach completion [2]. Similarly, Dr Steven Nissen (Cleveland Clinic, OH) questioned whether the trial would be completed because more than 5000 hard clinical end points are needed for the study to reach statistical significance, an unusually high number given that past studies required a few hundred events.

According to the IMPROVE-IT investigators, 18 000 patients will be enrolled in the clinical-outcomes study by June 2010.

Modest Absolute Reduction in Events Expected

In addition to providing an update on the trial's expected completion, the new IMPROVE-IT report, published as an editorial in the American Heart Journal by Dr Robert Califf (Duke University, Durham, NC) and colleagues, discusses the expected effect size of ezetimibe on cardiovascular events and why that effect will be valuable. Because of the background statin therapy, the group points out that the incremental absolute reduction in LDL cholesterol will be "modest," and as a result the anticipated absolute reduction in event rates will be modest also.

"The basic discussion is that we're playing on the end of the linear curve of what we know about the relationship between LDL-cholesterol lowering and clinical events," said Harrington. "We're down in an area where the absolute risk will be less than if your LDL cholesterol is higher. So the anticipated difference is obviously going to be less than it might be at a higher event rate. In some circles, people have said: 'Is this level of effect size valuable?' The retort from the committee is that given all of the controversy with ezetimibe, and given that this is the big clinical trial establishing outcomes, we think being pretty certain about the effect of ezetimibe is important."

Harrington told heartwire that the protocol design of the trial calls for an interim analysis when 50% of the events had occurred. They added a second interim analysis at 75% of events, and although the absolute reduction in events is expected to be modest, the second interim analysis makes it possible that the trial might be stopped early because of benefit.

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