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FDA briefing documents for on approval of edoxaban (Savaysa) for stroke prevention in atrial fibrillation raised questions of whether renal-sufficient people benefit as much from the drug and what dose to use for them.
"Given the availability of several NOACs [novel oral anticoagulants] that work well in people with normal renal function, it might be concluded that there is more work to do before edoxaban is approved," one of those documents said.
The FDA staffers offered no quibble with the overall results of the pivotal ENGAGE-AF trial, which showed noninferiority of 60- and 30-mg edoxaban versus well-managed warfarin (Coumadin, median time in therapeutic range 66%).
"The results of ENGAGE AF-TIMI 48 clearly demonstrate that edoxaban would provide physicians with a once-daily therapeutic option with a better bleeding profile than that provided by warfarin while maintaining a favorable reduction in the risk of stroke and systemic embolism," agency staff wrote.
But differences in efficacy when patients were stratified according to renal function have complicated the assessment and will surely be a major topic of discussion at the committee meeting.
And, for once, it is not patients with renal impairment who may be disallowed from taking a new drug, but rather those with normal function.
The Dose
Drugmaker Daiichi Sankyo requested approval of a 60-mg, once-daily dose as well as a 30-mg, once-daily dose for patients with moderate to severe renal impairment (creatinine clearance 15 to 50 mL/min), body weight under 132 lbs, or on P-glycoprotein inhibitors except amiodarone (Cordarone).
The FDA reviewers, though, pointed out that the lower dose trended toward inferiority, with a hazard ratio of 1.13 for stroke or systemic embolism versus warfarin (P=0.10).
"As there was no marked bleeding excess and bleeding rates were still well below warfarin, it seems hard to support use of a dose less than 60 mg," they explained.
They likened the results to those of dabigatran (Pradaxa) results in RE-LY, for which the lower 110-mg dose came close to being significantly worse for stroke and "which led to approval of only the 150-mg dose."
The Renal Issue
However, even the higher edoxaban dose was questioned for atrial fibrillation patients with normal renal function.
In ENGAGE-AF, the overall stroke hazard ratio with edoxaban at the higher 60-mg dose versus warfarin was 1.41 (95% confidence interval 0.97-2.05) with normal kidney function but 0.51 (95% CI 0.38-0.69) in the mildly-impaired renal subpopulation.
The FDA advisers called this a "clear difference" while acknowledging the issues raised by examining subsets.
"As edoxaban is renally excreted, renal function could affect blood levels and outcome, particularly when dose was not adjusted (people with normal and mildly reduced renal function both received 60 mg), even though higher blood levels would be expected in the mildly impaired group," they wrote.
The same pattern was seen for ischemic stroke: the hazard ratio for stroke was "markedly superior" with 60-mg edoxaban versus warfarin in the mildly impaired renal function group (HR 0.62, 95% 0.43-0.87) but worse with the factor Xa inhibitor in normal renal function (HR 1.58, 95% 1.02-2.45).
"For thromboembolic strokes (without help from reduced hemorrhagic strokes) the advantage for edoxaban in mild renal impairment still seems clear but, again, with removal of hemorrhagic strokes, the effect in patients with normal renal function seems even worse," the FDA review document noted.
A higher than tested dose might be better in the setting of normal renal function, it suggested.
"Modeling suggests an edoxaban dose of 75 to 90 mg would appear to provide an effect on thromboembolic stroke in patients with normal renal function similar to that seen in mild renal impairment, but these doses have not been given to patients," it pointed out.
"Although we regularly add lower dose recommendations to labeling to deal with renal or hepatic dysfunction or drug-drug interactions, we can think of no case where we have recommended a larger than studied dose; there are concerns about unexpected toxicity in such cases, although the higher blood levels that would occur have been used in patients; it is thus local effects that raise the principal concern."
It asked the advisory panel to consider whether the difference among the renal function subgroups might have reflected differences in exposure to edoxaban and what dose ought to be marketed for people with normal renal function if the drug were approved.
The question of whether to dose-adjust and monitor akin to warfarin, as raised by the BMJ investigation on dabigatran earlier this year, was not raised with edoxaban.
Daiichi Sankyo is also seeking approval for edoxaban for venous thrombosis indications, but the FDA is reviewing those separately and they will not be addressed in the Thursday session. The drug is currently approved in Japan for VTE prevention.
From the American Heart Association: