An advisory committee of the Food and Drug Administration, unconvinced of a clinically meaningful effect based on the IMPROVE-IT trial, voted against approving an expanded indication for ezetimibe (Zetia) in combination with simvastatin (Zocor).
Merck, which markets the combination as Vytorin in the United States, had come before the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) seeking an indication to reduce the risk of cardiovascular events in patients with coronary heart disease.
The committee’s 10-5 “no” vote came after a day of testimony and discussion that revolved around the results of the 18,000 patient, 7-year Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT). The trial enrolled patients soon after they had experienced an acute coronary syndrome (ACS) event. The sponsor’s presentation of the primary endpoint of the trial showed a modest treatment effect. For the composite primary efficacy endpoint of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke, for the patients randomized to receive simvastatin 40 mg plus ezetimibe 10 mg (Vytorin), compared with those on simvastatin 40 mg alone, the hazard ratio was 0.936 (95% confidence interval, 0.887-0.988; P = .016) (N Engl J Med. 2015 Jun 18;372:2387-97).
“From what I’ve heard today, I was not persuaded that the treatment effect was clinically meaningful,” said Dr. Sanjay Kaul, professor of medicine at the University of California, Los Angeles, and attending cardiologist at Cedars-Sinai Medical Center, also in Los Angeles. Other committee members were more blunt: Dr. Milton Packer, a distinguished scholar in cardiovascular science at Dallas’ Baylor University, said of the treatment effect, “You blink and you miss it.”
The effect size was more notable for two prespecified subgroups of the IMPROVE-IT population, those with diabetes and those aged 75 years and older. The meaning of the stronger effect in these two populations, who may have represented a higher risk subset of the larger study, was debated at length by the committee.
“Subgroup analyses are tempting but they can be treacherous,” said Dr. Kaul. “At this point, it is hard to ignore that 27% of the cohort is where most of the benefit is found. This is difficult to operationalize.”
The committee also expressed concern that follow-up for the primary endpoint was 91%, meaning that data were missing for thousands of patient-years of follow-up. “Missingness matters,” said Thomas R. Fleming, Ph.D., a professor in the department of biostatistics at the University of Washington, Seattle. “The goal of clinical research should be to obtain statistically reliable evidence regarding clinically meaningful effects,” and the missing data could endanger that reliability, he said.
Echoing the comments of several of the committee members who voted in favor of the expanded recommendations, Dr. Michael Blaha said “I think there’s a modest unmet need for add-on lipid-lowering therapy” for individuals with coronary disease. “The trial is positive, though the effect is modest. ... I voted ‘yes’ consistent with the way I would use it in clinical practice,” said Dr. Blaha, director of clinical research at the Ciccarone Center for the Prevention of Heart Disease at Johns Hopkins Hospital, Baltimore.
EMDAC chair Dr. Robert J. Smith, professor of medicine at Brown University, Providence, R.I., voiced the consensus of the committee in praising IMPROVE-IT as a “remarkable trial in terms of scope, duration, and quality.” Dr. Blaha pointed out that this was the trial that really showed that for cardiovascular risk and LDL levels, “Lower is better.”
The duration of the trial was noted by several committee members as giving reassuring information about the overall safety profile of ezetimibe/simvastatin. Some committee members, notably the patient representative Debra McCall of Murrieta, Calif., expressed concern about the slightly increased numbers of patients who suffered hemorrhagic stroke in the ezetimibe/simvastatin arm.
The FDA panelists were cleared of any potential conflicts of interest.
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