An FDA advisory committee has recommended unanimously that the ezetimibe-simvastatin combination pill (Vytorin) be approved for prevention of cardiovascular disease in CKD patients who are not on dialysis.…
In a second vote, the Endocrinologic and Metabolic Drugs Advisory Committee voted 10-6 against recommending approval for use of the drug in end-stage renal disease (ESRD) patients on dialysis. But several members of the panel said they wished they didn’t have to vote on each use separately.
“I find this an unfortunate way of phrasing things,” said Lawrence Hunsicker, MD, emeritus medical director of organ transplantation at the University of Iowa College of Medicine. “If you ask whether there should be an indication for end-stage renal disease, I have to say it’s not specifically effective in ESRD. On the other hand, if the question is phrased differently — Should ESRD be considered separately? I’d say no.”
The meeting focused on results from the SHARP study of the ezetimibe-simvastatin combination — available in a single tablet (Vytorin) or as separate products of ezetimibe (Zetia) and simvastatin (Zocor) — submitted to the agency by Merck/Schering-Plough, manufacturer of all three products, to support proposed label changes.
The company wants to be able to market Vytorin “to reduce the risk of major cardiovascular events in patients with CKD.”
SHARP (Study for Heart and Renal Protection), results of which were presented last November at a scientific meeting, found that the single-tablet treatment was associated with a 17% reduction in major atherosclerotic events and a 15% reduction in the risk of major vascular events, both compared with placebo (P<0.01 for both).
Nearly 9,500 patients participated in SHARP, in which patients were randomized in a 4:4:1 ratio to placebo, the combination treatment (Vytorin), or simvastatin alone. The combination treatment contained 10 mg of ezetimibe and 20 mg of simvastatin.
The study’s primary endpoint was the “first vascular event,” a composite of nonfatal MI, cardiac death, stroke, and any revascularization. For this endpoint, there was a reduction of 16.1% (P=0.001) in patients receiving the combination relative to placebo.
But although risk ratios for individual types of events all favored the ezetimibe-simvastatin combination, they failed to reach significance for cardiac death or nonfatal MI, FDA staff reviewers noted.
The lack of benefit for MI prevention did not seem to bother most of the panelists, however. “This is shown in [just about] every trial on cardiovascular disease, so I’m not at all surprised by this,” said Hunsicker. “The results are entirely consistent with what we’ve found in other studies of interventions of patients with heart disease.”
In addition, the group of patients on dialysis showed a smaller benefit in terms of lipid-lowering from the treatment, with an average relative reduction in LDL of 26%, compared with 34% in patients who were not on dialysis.
That result troubled some panelists. “None of us has seen a single large-scale trial that’s demonstrated a statistically significant reduction in cardiovascular events in patients on dialysis,” said panelist Michael Lauer, MD, director of cardiovascular sciences at the National Heart, Lung, and Blood Institute. “I’m much more comfortable saying it reduces risk in pre-dialysis patients.”
David Gordon, MD, PhD, MPH, special assistant for clinical studies at the National Heart, Lung and Blood Institute stated that, “In general, committee members praised the way the trial was conducted, especially its inclusion of patients without regard to their lipid levels at baseline.” “It was a strength of study that they included multiple lipids, and we wouldn’t have these data to talk about if they hadn’t done it.”
Several panel members noted that the trial included only a single dosage combination, and urged the agency to make it clear on the label that although Vytorin seems very safe at the dosage used, the safety of using the drug at higher doses is unknown.
The FDA is not obliged to follow recommendations of its advisory committees but it usually does.
FDA Advisory Committee Letter, Nov 2011