The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10 to 5 against recommending expanded indications for ezetimibe (Zetia, Merck) in conjunction with statin therapy and combination ezetimibe/simvastatin (Vytorin, Merck) to reduce the risk for cardiovascular (CV) events in patients with coronary heart disease.
The discussion centered on findings from the IMPROVE-IT trial, in which researchers examined the efficacy of ezetimibe 10 mg plus simvastatin 40 mg vs simvastatin 40 mg alone in patients who were hospitalized for an acute coronary syndrome in the preceding 10 days and had LDL cholesterol levels of 50 mg/dL to 100 mg/dL.
During follow-up (median, 6 years) the primary end point — a composite of CV death, nonfatal myocardial infarction (MI), unstable angina requiring rehospitalization, coronary revascularization (30 days or more after randomization), or nonfatal stroke — was reduced in the ezetimibe arm (HR=0.936; P=.016).1
In addition, researchers performed 23 subgroup analyses and found that the most favorable primary end point treatment effect was in patients with diabetes (HR=0.86; P=.001) or those aged at least 75 years (HR=0.80; P=.0003), whereas those without diabetes (HR=0.98; P=.49) or those younger than 75 (HR=0.97; P=.34) did not demonstrate any benefit with ezetimibe.2
During the panel meeting, the committee discussed several concerns with the data, including the magnitude of treatment effect in the primary end point analysis as well as the fact that approximately 11% of patients had missing data for the primary end point.
Although concerned by the missing data, panel member Sanjay Kaul, MD, professor at UCLA School of Medicine in Los Angeles, who voted against approval, commented that what was more important for him was the treatment effect, which he said was not statistically persuasive according to the regulatory statute.
“I had questions about the clinical meaningfulness of the treatment effect,” he said. “The most robust treatment effect was seen in an end point which was unfortunately an exploratory endpoint, hence may most be used for claim: [in] CV death, nonfatal MI and nonfatal stroke, we see a 10% relative reduction with a P value that is .003; quite robust, but unfortunately that is not approvable for a claim.”
Brendan M. Everett, MD, MPH, panel member and assistant professor of medicine at Harvard Medical School in Boston, who voted in favor of approval, said that in the case of IMPROVE-IT, “perfect is the enemy of very good.”
“It is just not possible to do a perfect trial and get the perfect answer to the clinical question,” he said. “So … from my standpoint, [IMPROVE-IT] represents substantial evidence to support approval.”
Panel member Milton Packer, MD, distinguished scholar in cardiovascular science at Baylor University Medical Center in Dallas, who voted against approval, said that clinicians who want to use ezetimibe for risk reduction in CV disease can do so now based on the current label.
“You have a label for this drug that says you can use it for cholesterol lowering,” Dr Packer said. “And if you believe that cholesterol lowering lowers CV risk, then IMPROVE-IT supports that … and you don’t need a label change.”
Furthermore, the committee cautioned against drawing conclusions based on the findings of the subgroup analyses in patients with diabetes and those aged at least 75, due to the inherent limitations and hazards.
“One has to be very careful with secondary analyses of subgroups, particularly when we are looking at so many,” said Michael J. Blaha, MD, MPH, panel member and assistant professor at Johns Hopkins Hospital in Baltimore, who voted in favor of approval. “The notion I take away is to not over-read into this and that perhaps higher-risk groups get more benefit.”
The FDA is not required to follow the advisory committee’s recommendations.
Disclosures: The FDA panel members report no relevant conflicts of interest.
- Cannon CP, Blazing MA, Giugliano RP, et al; for the IMPROVE-IT Investigators. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387-2397.
- U.S. Food and Drug Administration. FDA Briefing Documents for the December 14, 2015 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC). December 14, 2015. Accessed December 14, 2015.