FDA Review Backs Vytorin in Kidney Disease Patients

Combinations of ezetimibe and simvastatin help reduce cardiovascular events in patients with chronic kidney disease (CKD), the FDA's professional staff indicated in briefing documents prepared for an advisory committee meeting later this week.

The FDA reviewers found little fault with data from the so-called 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 cheap jerseys free shipping by Merck/Schering-Plough, manufacturer of all three products, to support proposed label changes.

The company wants to be able to market the products "to reduce the risk of major cardiovascular events in patients with CKD."

SHARP (Study for Heart and Renal Protection), results cheap football jerseys 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 study's primary endpoint was the "first vascular event," a composite of nonfatal myocardial infarction, cardiac death, stroke, and any revascularization.

For this endpoint, there was a reduction of 16.1% cheap baseball jerseys (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, the FDA reviewers noted.

Consequently, the agency plans to ask members of the NHL Jerseys Cheap Endocrinologic and Metabolic Drugs Advisory Committee on Wednesday to comment on the use of a composite outcome as a primary endpoint.

The review also highlighted the greater benefit of the combination in patients not yet on dialysis, with a risk ratio for the primary outcome of 0.77 (95% CI 0.67 to 0.88) versus 0.94 (not significant) among dialysis patients.

The meeting agenda will include separate voting questions snsbars on whether the ezetimibe-simvastatin combination should be approved in pre-dialysis and dialysis patients with CKD.

Another question for the committee to address involves the definition of CKD used in SHARP, under which 94% of pre-dialysis patients enrolled in the study had estimated glomerular filtration rates of less than 45 mL/min/1.73 m2.

"Individuals with an estimated GFR [at that level] represent cheap nfl jerseys 15% of the entire CKD population in the United States," the review noted.

As a result, FDA officials plan to ask the committee to consider these entry criteria and whether the SHARP results can appropriately be generalized to the overall pre-dialysis CKD population.

FDA staff appeared to accept the safety results in SHARP, which generally were favorable. No increases in cancer diagnoses, liver enzyme elevations, or serious adverse events overall were seen with the drug combination relative to placebo.

Myopathy was somewhat more common but was still rare (nine cases versus five in the placebo group). And discontinuations because of nonserious adverse events were more frequent with ezetimibe-simvastatin (3.5% versus 2.8%).

The FDA is not obliged to follow recommendations of its advisory committees but it usually does.

The combination of ezetimibe and simvastatin has been controversial since the ENHANCE trial failed to find a benefit for it relative to the statin alone.

Merck had been hoping that SHARP, and another larger trial called IMPROVE-IT, would show a clear benefit for the addition of ezetimibe, which has fallen into disfavor in the wake of ENHANCE.

IMPROVE-IT, with planned enrollment of more than 18,000, is supposed to finish in 2013.
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Ezetimibe was approved as a solo cholesterol-lowering drug in 2002. The Vytorin combination was approved two years later. Currently, the latter's label states that "no incremental benefit of Vytorin on cardiovascular morbidity and mortality over and above that demonstrated for simvastatin has been established."