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FDA advisory panel recommends approval of edoxaban for prevention of stroke, systemic embolism
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The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 9-1 to recommend that edoxaban, a novel oral anticoagulant, be approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation.
However, the panel was split over issues of dosage and renal function. ENGAGE AF–TIMI 48 trial results indicated that edoxaban (Daiichi Sankyo) was more effective in patients with mildly or moderately impaired renal function than in patients with normal renal function.
The FDA asked panelists who voted to approve the drug whether the 60 mg/day dose recommended by the sponsor should be approved for all patients with nonvalvular AF; whether a dose higher than 60 mg/day, which was not studied in ENGAGE AF–TIMI 48, should be approved for appropriate patients with normal renal function; or whether approval of the drug should be indicated only for appropriate patients with mild or moderate renal impairment.
Panel split over appropriate patient population
Of the nine panelists who voted to approve the drug, five said that they preferred the first of the above options, two said they preferred the second and two said they preferred the third option.
“This was a hard choice, but when I looked at the totality of the data, I remained concerned with the decreased efficacy in the normal renal function group,” panelist Phillip Sager, MD, of Stanford University School of Medicine, said. “It’s more likely than not to be a real finding, and that could subject those patients to an increased risk of strokes. Given that, at this moment, I would go with [approval only for] patients with mild and moderate renal impairment. However, it’s possible with more data that [approval of a higher dose for patients with normal renal function] might also be an option.”
A. Michael Lincoff
Panel chairman A. Michael Lincoff, MD, of Cleveland Clinic, said that while he shared Sager’s concerns, “I’m a little bit more comfortable with the idea of relatively rapidly produced pharmacokinetic data that would support [approval of a higher dose for patients with normal renal function].”
Panelist Jeffrey S. Borer, MD, of State University of New York Downstate Medical Center, New York, said that approval for all patients with nonvalvular AF was appropriate as long as “we put the information about what’s known from the trial in the label. I see no reason not to do that.”
One of many treatment choices
The lone “no” vote was cast by Stuart Rich, MD, of University of Chicago Pritzker School of Medicine, who said he would only be comfortable with approval for patients with mildly or moderately impaired renal function, “but then, if the renal function gets better, now what do I do? Are there any other choices? Well, there are a lot of other choices. What do I need this drug for, then? I’m only going to get into trouble.”
Among patients with normal renal function, the event rate for all strokes in ENGAGE AF–TIMI 48 was 1.07% per year for patients assigned high-dose edoxaban vs. 0.76% per year for patients assigned warfarin (HR=1.41; 95% CI, 0.97-2.05). Among patients with mildly or moderately impaired renal function, the event rate was 1.04% per year for patients assigned high-dose edoxaban vs. 2.01% per year for those assigned warfarin (HR=0.51; 95% CI, 0.38-0.69). Patients with severely impaired renal function were excluded from the trial.
If approved, edoxaban would be the fourth novel oral anticoagulant on the market in the United States for prevention of stroke and systemic embolism in this patient population. The FDA is not required to follow the recommendations of its advisory panels, but it usually does.
For more information:
CRDAC Clinical Briefing Document. NDA 206316.
Disclosure: The members of the Cardiovascular and Renal Drugs Advisory Committee report no relevant financial disclosures.