[UPDATED]SILVER SPRING, MD. – Vytorin should be approved for preventing major vascular events in patients who have chronic kidney disease but are not on dialysis, according to a unanimous vote by a Food and Drug Administration advisory panel.
The panel also voted 10-6, however, that the safety and effectiveness data did not support approval of the combination of 10 mg of ezetimibe with 20 mg of simvastatin for the same indication in patients with end-stage renal disease who are on dialysis.
Their votes at the Nov. 2 meeting were based on the results of the Study of Heart and Renal Protection (SHARP), which evaluated the effects of reducing LDL cholesterol on the risk of coronary vascular disease in patients with chronic kidney disease who are at an increased risk of cardiovascular morbidity and mortality. About two-thirds of the patients in the trial were not on dialysis at baseline, and in these patients, there was a 23% reduction in the primary end point – the risk of a major vascular event (nonfatal MI or cardiac death, stroke, or a revascularization procedure that excluded dialysis access-related procedures) – compared with those on placebo over a mean of 5 years (Lancet 2011;377:2181-92).
But in the patients who were on dialysis at baseline, the risk was reduced by about 6% over placebo. Panelists who did not support approval in this group cited the lower degree of effectiveness, and the fact that end stage renal disease patients on dialysis are very different from predialysis patients – and that patients with ESRD in the United States are different than those elsewhere. They noted that only 4% of the patients in SHARP were in the United States, and management and outcomes of patients with ESRD are different in the United States than in other parts of the world.
Dr. Lamont Weide
Dr. Lamont Weide, chief of diabetes and endocrinology, at the University of Missouri, Kansas City, backed approval for predialysis patients, but not for those on dialysis. Like several other panelists, he also considered the results of two previous large studies of about 4,000 CKD patients on dialysis, which found no significant beneficial effects of treatment with other statins on cardiovascular outcomes. While these were three different studies with different agents and different entry criteria, he said that the results go in the same direction as SHARP, in a large group of patients "without any clear indication of benefit." Those studies were the 4D study (N. Engl. J. Med. 2005;353:238-48) and the AURORA study (N. Engl J. Med. 2009;360:1395-407).
Also splitting her votes, Dr. Julia Lewis, professor of medicine in the department of nephrology, Vanderbilt University, Nashville, referred to those two trials and added that she considers her dialysis patients considerably different than her clinic patients who are not on dialysis. She commended the SHARP study and investigators for "providing what I think is going to be a wonderful addition to the care of CKD patients. It is going to change care of CKD patients and prevent the bad [cardiovascular] outcomes that affect them," she said.
In the study overall, the risk of major vascular events was reduced by 16% among those treated with the combination as compared to those on placebo, which was primarily driven by a reduction in the revascularization component. Cancers and all-cause mortality were similar in treated patients and those on placebo, and the panel agreed there were no new safety concerns at the dose studied. (About one-quarter of those enrolled died during the study.)
Merck, the manufacturer of ezetimibe (Zetia) and Vytorin, filed for approval of the claim that 10 mg of ezetimibe plus 20 mg of simvastatin (in the fixed-dose combination pill or taken separately) reduces the risk of major cardiovascular events in patients with chronic kidney disease on the basis of the SHARP results. SHARP was funded by Merck and Schering-Plough, but was independently conducted by the Oxford (England) University Clinical Trials Service Unit. Ezetimibe was used to make it possible to use a lower dose of simvastatin in the CKD patients, who are at a greater risk of myopathy and other adverse effects of statins.
Panelists emphasized that the 10 mg of ezetimibe with the 20-mg dose of simvastatin was the dose combination studied and was shown to be safe, and that doses should not be increased in this population of patients.
Dr. William R. Hiatt
The two drugs are only approved for lipid-lowering indications: Ezetimibe, a selective inhibitor of the absorption of intestinal cholesterol and related phytosterol marketed as Zetia, was approved by the FDA in 2002; Vytorin, a combination of ezetimibe and the HMG-CoA reductase inhibitor simvastatin was approved in 2004; simvastatin was approved in 1991.