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FDA Advisors Back Limited Use of Blood Thinner Edoxaban

Once-daily pill works best in patients with abnormal kidney function

The FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) has recommended approval of a 60-mg dose of the blood thinner edoxaban (Savaysa, Daiichi Sankyo) for patients with non-valvular atrial fibrillation (NVAF), but suggested limiting its use to those with abnormal kidney function (i.e., creatinine clearance < 80 mL/min).

Edoxaban is a once-daily anticoagulant that inhibits factor Xa, a protein that plays a key role in blood-clotting.

The report comes 2 days ahead of a scheduled meeting of independent experts, who will discuss the drug and recommend whether it should be approved.

While the FDA is not obligated to follow the recommendations of its advisory committees, it usually does so.

The regulatory submission for edoxaban was based on results from the ENGAGE-AF-TIMI 48 trial. This large, non-inferiority, double-dummy study compared two dosing regimens of edoxaban –– a high-exposure arm and a low-exposure arm –– with warfarin in approximately 21,000 adults with NVAF. In the edoxaban high-exposure arm, the dosage for most subjects was 60 mg once daily (OD); in the low-exposure arm, it was 30 mg OD. In both treatment arms, patients who met one or more of three dose-reduction criteria (creatinine clearance ≤ 50 mL/min, weight ≤ 60 kg, or use of specified P-glycoprotein–inhibiting drugs) were treated with half the usual dosage (i.e., with 30 mg OD or 15 mg OD in the high- and low-exposure arms, respectively). Warfarin dosing was based on the international normalized ratio (INR), with a target of 2.0 to 3.0.

Both the edoxaban high-exposure regimen and the edoxaban low-exposure regimen were non-inferior to warfarin for the trial’s primary endpoint: the time to the composite of stroke (any type) or systemic embolism.

However, the FDA advisors noted that efficacy outcomes by baseline renal function had potential implications for approval or labeling. In subjects with normal renal function, defined as estimated creatinine clearance ≥ 80 mL/min, the hazard ratio for the primary endpoint favored warfarin over the edoxaban high-exposure regimen (hazard ratio: 1.41). This represented a reversal of the results observed in the overall trial results and in subgroups with impaired renal function. Results for the low-exposure arm showed the same pattern of worsened results for edoxaban in patients with normal renal function.

Similarly, the effect of edoxaban on ischemic stroke compared with warfarin was neutral overall for the high-exposure group but was substantially reduced in subjects with normal renal function.

After considering the overall trial data and the subgroup analyses, the advisory panel recommended approval of edoxaban 60 mg OD in patients with NVAF, with a limitation of use to patients with abnormal renal function (i.e., creatinine clearance < 80 mL/min).

If approved, edoxaban will compete with other drugs in its class, including rivaroxaban (Xarelto, Bayer/Janssen) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer). It will also compete with dabigatran etexilate (Pradaxa, Boehringer Ingelheim). However, the FDA advisors noted that edoxaban has no proven advantages over any of these direct-acting anticoagulants approved for stroke prevention in patients with atrial fibrillation.

On the plus side, edoxaban is an OD pill, like rivaroxaban, whereas apixaban and dabigatran are dosed twice daily.

Sources: FDA; October 28, 2014; and Reuters; October 28, 2014.

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