FDA Advisory Panel Votes 9 to 1 in Favor of Edoxaban for Stroke Prevention in AF Patients

October 30, 2014

SILVER SPRING, MD ( updated )— A US Food and Drug Administration (FDA) advisory panel voted overwhelmingly in favor of another novel anticoagulant for the treatment of patients with atrial fibrillation (AF)[1].

The Cardiovascular and Renal Drugs Advisory Committee voted 9 to 1 in favor of approving edoxaban (Savaysa, Daiichi-Sankyo), a factor Xa inhibitor, for the prevention of stroke and non–central-nervous-system (CNS) systemic embolism in patients with nonvalvular AF.

Throughout today's advisory committee meeting, FDA panel members analyzed and debated data from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, a large, event-driven study in 21 105 patients with nonvalvular AF. In the study, which was reported by heartwire , once-daily therapy with edoxaban at either of two dosages was noninferior to warfarin for preventing stroke or systemic embolism in nonvalvular AF patients. Both edoxaban daily dosages, 60 mg and 30 mg, were associated with significantly less major bleeding than the vitamin-K antagonist in the trial.

The Issues Before the FDA Advisory Panel

One of the major issues that arose during the daylong panel discussion pertained to a subgroup analysis. In ENGAGE AF, an analysis stratified by renal function showed that patients with a creatinine clearance >80 mL/min did not fare as well on treatment as those with abnormal renal function.

Regarding the primary efficacy end point—which was the time to the first adjudicated stroke (ischemic or hemorrhagic) or systemic embolic event—individuals with a creatinine clearance >80 mL/min fared significantly worse when treated with the 30-mg dose of edoxaban. In patients treated with the 60-mg dose, the results showed the same pattern. Overall, the hazard ratio for the primary end point vs warfarin was 1.41 (95% CI 0.97–2.05) for individuals with normal renal function treated with 60 mg of edoxaban.

As part of the discussion, the FDA committee members were asked for their interpretation of the primary efficacy end point, ischemic stroke, and bleeding results in subgroups based on renal function and whether or not they thought the findings were real or the play of chance.

Dr Linda Fried (University of Pittsburgh, PA), a nephrologist, said she was not 100% confident the results were caused by drug exposure—50% to 60% of edoxaban is excreted by the kidneys, making individuals with normal renal function more likely to be underexposed to treatment—but she does suspect the results were real. Acknowledging the inherent difficulties in interpreting subgroups, especially when they run counter to the overall findings, Fried said the lack of benefit in patients with normal renal function is biologically plausible.

Panel member Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles) acknowledged that subgroup analyses "can be tempting, but treacherous." That said, he also believes the difference in outcomes based on renal function to be a real finding. "The FDA is in a tight position," said Kaul. "It's put in a position that could, if it's the wrong decision, have tremendous public impact. From a statistical and methodological perspective, I think this is a proper subgroup. It's prespecified. It's a large subgroup. It's a prerandomization subgroup. And it's a clinically plausible subgroup. We can explain away the reason that the efficacy outcomes are not as robust."

What Dosages Should Be Approved?

Given the subgroup analysis, this led to discussions about whether or not the FDA should approve a dose higher than 60 mg, one that was not tested in ENGAGE AF. The higher dose (a 90-mg dose was used in phase 2 studies) would be based on analyses showing a relationship between serum concentrations of edoxaban and the study's safety and efficacy outcomes.

Dr Jeffrey Borer (State University of New York, NY), along with the majority of panel members, said he'd have problems approving a dose not tested in the randomized clinical trial. "I'd be concerned about adverse events we can't predict over time," said Borer. At the higher dose, the risk/benefit profile—increased risk of major bleeding coupled with a reduction in stroke—would be a big unknown. "It is a fact of life with these drugs that as you do better at preventing thrombotic stroke, you cause more bleeding," commented panelist Dr Philip Sager (Stanford University School of Medicine, CA).

Given the questions surrounding dose and the renal-function subgroup, the panel was somewhat divided on the need for further postmarketing studies or appropriate labeling and packaging should the drug be approved. The committee members were asked their take on what steps would be needed to prevent patients with normal renal function from receiving the drug should only the 60-mg dose be approved. Borer suggested a "Dear Doctor" letter warning about the lack of efficacy in this subgroup. Physicians would pay attention to such a letter, he said, noting that doctors, for the most part, "don't read labels."

Dr Stuart Rich (University of Chicago Pritzker School of Medicine, IL) was the lone dissenter on the approval vote. He considered voting yes if the drug were available only to patients with mild and moderate renal impairment, but such an approval might leave physicians in a bind if renal function improves. Given the possibility of such a difficult scenario, he questioned whether he'd need edoxaban, given the availability of other anticoagulants, such as rivaroxaban (Xarelto, Bayer) and apixaban (Eliquis, Pfizer/Bristol Myers-Squibb), which are both approved for stroke prevention in AF. Dabigatran (Pradaxa, Boehringer Ingelheim), a direct-thrombin inhibitor, is also available.

"There are a lot of other [novel oral anticoagulants] NOACs out there," said Rich. "What do I even need this drug for? I'm only going to get into trouble. I hate stroke. I don't care if it's ischemic or hemorrhagic. I hate it. So I voted no."

As part of its own independent review, the FDA also acknowledged the existence of other anticoagulants, noting that two (dabigatran, apixaban) have superiority claims compared with warfarin, whereas edoxaban showed only noninferiority in ENGAGE AF. As the reviewers pointed out, it raises the possibility that edoxaban might displace more effective therapy. Despite this, the FDA review notes that edoxaban "came close to achieving superiority" in ENGAGE, and "it is not reasonable to conclude that edoxaban is inferior to dabigatran or apixaban in the overall nonvalvular AF patient population.


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