Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial

Bohula EA, Giugliano RP, Ruff CT, et al.
Circulation. 2016;134:24-36

Background

Edoxaban, an oral factor Xa inhibitor, is non-inferior to warfarin for the prevention of thromboembolic events in patients with atrial fibrillation (AF), and is associated with significantly lower major bleeding rates, based on the results of the ENGAGE AF-TIMI 48 trial [1].

The higher-dose edoxaban regimen (HDER), 60 mg once daily, is approved for AF patients, but there is a label restriction for patients with creatinine clearance (CrCl) > 95 mL/min, because of the open question of decreased relative efficacy for the prevention of ischemic stroke compared with warfarin [2,3]. Due to the significant renal clearance of edoxaban, AF patients with renal dysfunction were either excluded from the ENGAGE AF-TIMI 48 study if they had CrCl < 30 mL/min, or received a lower edoxaban dose (30 mg once daily), if they had CrCl 30-50 mL/min and low body weight or concomitant use of a potent phosphorylated glycoprotein inhibitor [4].

In this pre-specified analysis of the ENGAGE AF-TIMI 48 study, the efficacy, safety, and net clinical outcomes with HDER compared with warfarin was evaluated based on renal function.

Main results

The absolute rates of the primary efficacy end point of stroke/systemic embolism (S/SE) were:  

• in patients with moderate renal dysfunction (CrCl 30–50 mL/min): 2.3%/year for HDER and 2.7%/year for warfarin
• in patients with mild or no renal dysfunction (CrCl >50 mL/min): 1.4%/year for HDER and 1.6%/year for warfarin

The efficacy of HDER and warfarin were similar (P for interaction by renal function=0.94):

• for CrCl of 30–50 mL/min: HR: 0.87; 95%CI: 0.65–1.18
• for CrCl >50 mL/min: HR: 0.87; 95%CI: 0.72–1.04

HDER was superior to warfarin for the primary safety end point in both renal subgroups (P for interaction by renal function = 0.62):

• for CrCl of 30–50 mL/min: HR: 0.76; 95%CI: 0.58–0.98
• for CrCl >50 mL/min: HR: 0.82; 95%CI: 0.71–0.95

Patients with moderate renal dysfunction at baseline were at higher risk for the primary net clinical outcome of S/SE, major bleeding, or death:

• for CrCl of 30–50 mL/min: 11.4%/year for HDER and 13.4%/year for warfarin
• for CrCl >50 mL/min: 6.3%/year for HDER and 7.0%/year for warfarin

HDER resulted in a more favourable net clinical outcome compared with warfarin regardless of renal function (P for interaction by renal function=0.49):

• for CrCl of 30–50 mL/min: HR: 0.86; 95% CI: 0.75–0.98
• for CrCl >50 mL/min: HR: 0.91; 95% CI: 0.83–0.99

An evaluation of the 3 subgroups defined by CrCl of 30 to 50, >50 to 95, and >95 mL/min found a nonsignificant trend toward differential relative efficacy for the primary end point with HDER vs. warfarin across renal subgroups (P for interaction=0.08 for renal function subgroups by treatment):

• for CrCl of 30–50 mL/min: HR: 0.87; 95% CI: 0.65–1.18
• for CrCl >50–95 mL/min: HR: 0.78; 95% CI: 0.64–0.96
• for CrCl >95 mL/min: HR: 1.36; 95% CI: 0.88–2.10

The primary net clinical outcome of S/SE, major bleeding, and all-cause death was, although not significant, more favourable for HDER compared with warfarin across the range of renal function subgroups (P for interaction by renal function=0.73):

• for CrCl 30–50 mL/min; HR: 0.86; 95% CI: 0.75–0.98
• for CrCl >50–95 mL/min: HR: 0.91; 95% CI: 0.82–1.00
• for CrCl >95 mL/min: HR: 0.93; 95% CI: 0.77–1.13

Conclusion

In the ENGAGE – AF TIMI 48 trial, 60 mg edoxaban daily showed comparable efficacy and better safety compared with warfarin, both in AF patients with, or without moderate renal dysfunction. However, exploratory analyses showed a lower relative efficacy for the prevention of stroke or systemic embolism in patients with CrCl >95 mL/min, therefore the optimal dosing of edoxaban in these patients needs further investigation.

Find this article online at Circulation

References

1. Giugliano RP, Ruff CT, Braunwald E, et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104.
2. US Food and Drug Administration. Prescribing information for Savaysa (edoxaban). 2015. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf. Accessed January 27, 2016.
3. Lixiana: EPAR-product information. 2015. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/
human/002629/WC500189045.pdf. Accessed January 28, 2016.
4. Salazar DE, Mendell J, Kastrissios H, et al. Modelling and simulation of edoxaban exposure and response relationships in patients with atrial fibrillation. Thromb Haemost.2012;107:925–936.