Anticoagulation With Edoxaban: When to Worry

Devada Singh-Franco, PharmD

Disclosures

March 02, 2016

Question

What factors affect a patient's bleeding risk with edoxaban?

Response from Devada Singh-Franco, PharmD
Associate Professor, Department of Pharmacy Practice, Nova Southeastern University College of Pharmacy; Ambulatory Care Pharmacist, Broward Health Medical Center, Fort Lauderdale, Florida

Edoxaban, a reversible and direct inhibitor of factor Xa, is used to reduce the risk for stroke and systemic embolism in patients with nonvalvular atrial fibrillation (NVAF). It is also used to prevent and treat venous thromboembolism, which includes deep vein thrombosis and pulmonary embolism.[1,2]

Compared with warfarin, edoxaban has fewer food and drug interactions and is administered as a fixed daily dose.

Unlike with warfarin, laboratory monitoring for the anticoagulant effect of edoxaban is not routinely performed because anti-factor Xa assays may not be accurate or reliable at higher on-therapy edoxaban concentrations. Although a prolonged prothrombin time (PT) may be considered evidence of circulating edoxaban levels, a normal PT does not exclude clinically relevant on-therapy drug levels.[3] Therefore, dose reduction to limit edoxaban exposure must be guided by patient-specific factors, such as body weight, renal function, concurrent medications, and risk for gastrointestinal (GI) bleeds, rather than laboratory values.

Body weight. In a 3-month study to determine the incidence of bleeding with two fixed dosages of edoxaban (30 mg/day or 60 mg/day) in patients with NVAF in four Asian countries (Taiwan, South Korea, Hong Kong, and Singapore), bleeding rates were higher for patients weighing ≤60 kg in both edoxaban groups compared with patients weighing >60 kg (odds ratio, 2.38; 95% confidence interval, 1.01-5.62; P=.048).[4]

In the ENGAGE-AF TIMI 48 study, conducted worldwide, dose adjustments were made based on renal function or low body weight.[5] The assigned dose (60 mg or 30 mg) was halved (to 30 mg or 15 mg) for patients with creatinine clearance (CrCL) 30-50 mL/min or who weighed ≤60 kg. In patients who had dosage reductions, the efficacy of edoxaban in preventing stroke or systemic embolic events was noninferior to warfarin, with a lower risk for major bleeding.[5,6] However, only high-dose edoxaban (60 mg if CrCL is 51-95 mL/min and body weight >60 kg or 30 mg if CrCL is 30-50 mL/min or body weight ≤60 kg) was as effective as warfarin in reducing the incidence of ischemic stroke.[5,6]

Renal impairment. Renal excretion accounts for about 50% of total edoxaban elimination; renal impairment increases exposure to edoxaban and can lead to increased bleeding risk.[1,7] A single 15-mg dose of edoxaban increases systemic exposure by 32% with mild impairment (CrCL 50-80 mL/min), 74% with moderate impairment (CrCL 30-49 mL/min), 72% with severe impairment (CrCL <30 mL/min), and 93% with peritoneal dialysis, compared with normal renal function. The mean half-life increased from 8.6 hours with normal renal function to 9.4 hours with moderate impairment, 16.9 hours with severe impairment, and 12.2 hours with peritoneal dialysis.[8]

Dosage should be adjusted for reduced renal function to reduce bleeding risk.[4] If CrCL is 51-95 mL/min, initiate therapy at 60 mg/day, with or without food; if CrCL is 15-50 mL/min, initiate therapy at 30 mg/day.[1] If CrCL is >95 mL/min, another anticoagulant should be prescribed due to lower edoxaban serum levels and increased risk for ischemic events compared with warfarin.[1] Hemodialysis does not significantly remove edoxaban from the blood; hence, a supplementary dose may not be required post-dialysis.[9]

Hepatic impairment. Edoxaban is also cleared by hepatobiliary pathways with minimal metabolism. Less than 4% is metabolized via CYP3A4, and less than 10% is formed into an active metabolite (M4) by carboxylesterase. Population pharmacokinetic modeling of data from subjects with renal impairment and normal hepatic function who received a single 15-mg dose of edoxaban showed that the concentrations of edoxaban and M4 increased in parallel with decreasing kidney function, but the ratio of M4 over edoxaban exposure remained constant.[10] In subjects with normal renal function (CrCL ≥60 mL/min) and mild-to-moderate hepatic impairment (Child-Pugh Grade A and B) who received a single 15-mg dose of edoxaban, edoxaban and M4 exposures were not significantly different from matched controls.[11]

In the ENGAGE-AF TIMI 48 study, subjects with active liver disease or persistent elevation of liver enzymes/bilirubin were excluded.[5] There are no current recommendations for use of edoxaban in patients with severe hepatic impairment.

Drug interactions. Edoxaban is a substrate of P-glycoprotein (P-gp) transporter, and interaction with strong P-gp inhibitors can lead to increased edoxaban exposure.[1,12] In the ENGAGE-AF TIMI 48 study, the assigned dose (60 mg or 30 mg) was halved for a small proportion of patients receiving quinidine, verapamil, or dronedarone; however, dose reduction resulted in lower edoxaban blood levels and anti-factor Xa activity with an increased risk for stroke or systemic embolic event, although the total number of events (28) was small.[6] Therefore, dose reduction in a patient who is also receiving concomitant P-gp inhibitors is not recommended.[1] Patients receiving other potent P-gp inhibitors, such as ritonavir, cyclosporine, ketoconazole, itraconazole, erythromycin, and clarithromycin, were excluded from the ENGAGE-AF TIMI 48 study.[5]

About 12% of patients in the ENGAGE-AF TIMI 48 study received concomitant amiodarone, a modest P-gp inhibitor, at baseline without edoxaban dosage adjustments. Edoxaban trough levels were significantly higher in patients receiving concomitant amiodarone (P<.001), and clinically relevant nonmajor bleeds with high-dose edoxaban were more frequent compared with warfarin (P=.012 for interaction), but nonmajor bleeds did not increase in the low-dose edoxaban group.[13] The risk for major bleeding (the principal safety endpoint) was not increased with high-dose edoxaban; therefore, no dosage adjustment of edoxaban is recommended for a patient receiving concomitant amiodarone.[1]

Rifampin, a strong P-gp inducer, reduced exposure to edoxaban while increasing exposure to its active metabolites.[14] Package labeling recommends against concurrent use.[1]

GI bleeds. In the ENGAGE-AF TIMI 48 study, GI bleeds occurred more frequently with high-dose (60 mg) edoxaban than with warfarin (hazard ratio, 1.23; P=.03) but less frequently with low-dose (30 mg) edoxaban (hazard ratio, 0.67; P<.001).[5] Gastroprotection could be considered for patients with a history of GI ulcer/bleed, advanced age, and concomitant use of aspirin, nonsteroidal anti-inflammatory drugs, and corticosteroids.[15,16]

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