BACKGROUND: Managing patients with atrial fibrillation (AF) and worsening renal function (WRF) remains a clinical challenge due to the need of dose adjustment of non-vitamin K antagonist oral anticoagulants. OBJECTIVES: To determine the incidence of WRF in patients with AF treated with edoxaban, the association of WRF with clinical outcomes, and predictors of WRF and clinical outcomes in these patients. METHODS: This is a subanalysis of the Edoxaban Treatment in routiNe clinical prActice for patients with non-valvular Atrial Fibrillation in Europe study (NCT02944019), an observational study of edoxaban-treated patients with AF. WRF was defined as a ≥25% reduction in creatinine clearance between baseline and 2 years. RESULTS: Of the 9,054 patients included (69% of the total 13,133 enrolled), most did not experience WRF (90.3%) during the first 2 years of follow-up. WRF occurred in 9.7% of patients. Patients with WRF had significantly higher rates of all-cause death (3.88%/y vs 1.88%/y; P < 0.0001), cardiovascular death (2.09%/y vs 0.92%/y; P < 0.0001), and major bleeding (1.51%/y vs 0.98%/y; P = 0.0463) compared with those without WRF. Rates of intracranial hemorrhage (0.18%/y vs 0.18%/y) and of any stroke/systemic embolic events were low (0.90%/y vs 0.69%/y; P = 0.3161) in both subgroups. The strongest predictors of WRF were a high CHA2DS2-VASc score, high baseline creatinine clearance, low body weight, and older age. Most predictors of WRF were also predictors of clinical outcomes. CONCLUSIONS: WRF occurred in approximately 10% of edoxaban-treated AF patients. Rates of death and major bleeding were significantly higher in patients with WRF than without. Stroke events were low in both subgroups.

Amsterdam Cardiovascular Sciences Heart Failure and Arrhythmias Amsterdam the Netherlands

Amsterdam University Medical Centers University of Amsterdam Amsterdam the Netherlands

Cardiology Division University of Pisa Pisa Italy

Daiichi Sankyo Austria GmbH Vienna Austria

Daiichi Sankyo Europe GmbH Munich Germany

Department of Cardiology Medical University of Vienna Vienna Austria

Department of Cardiology Rijnstate Hospital Arnhem the Netherlands

Department of Immunochemistry Diagnostics University Hospital Pilsen Pilsen Czech Republic

Fondazione VillaSerena per la Ricerca Pescara Italy

German Center for Cardiovascular Sciences Partner Site Hamburg Kiel Lübeck Hamburg Kiel Lübeck Germany

Institute of Cardiovascular Sciences University of Birmingham Birmingham UK

Institute of Computer Science of the Czech Academy of Sciences Prague Czech Republic

University Heart and Vascular Centre Hamburg University Medical Centre Hamburg Eppendorf Hamburg Germany

Virgen del Rocio University Hospital University of Seville Seville Spain

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Ravera M., Bussalino E., Fusaro M., et al. Systematic DOACs oral anticoagulation in patients with atrial fibrillation and chronic kidney disease: the nephrologist's perspective. J Nephrol. 2020;33:483–495. PubMed

Goto S., Angchaisuksiri P., Bassand J.P., et al. Management and 1-year outcomes of patients with newly diagnosed atrial fibrillation and chronic kidney disease: results from the prospective GARFIELD - AF registry. J Am Heart Assoc. 2019;8 PubMed PMC

Ding W.Y., Gupta D., Wong C.F., Lip G.Y.H. Pathophysiology of atrial fibrillation and chronic kidney disease. Cardiovasc Res. 2021;117:1046–1059. PubMed

Yao X., Tangri N., Gersh B.J., et al. Renal outcomes in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2017;70:2621–2632. PubMed

De Caterina R., Kelly P., Monteiro P., et al. Design and rationale of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study. J Cardiovasc Med (Hagerstown) 2019;20:97–104. PubMed

De Caterina R., Kelly P., Monteiro P., et al. Characteristics of patients initiated on edoxaban in Europe: baseline data from edoxaban treatment in routine clinical practice for patients with atrial fibrillation (AF) in Europe (ETNA-AF-Europe) BMC Cardiovasc Disord. 2019;19:165. PubMed PMC

de Groot J.R., Weiss T.W., Kelly P., et al. Edoxaban for stroke prevention in atrial fibrillation in routine clinical care: 1-year follow-up of the prospective observational ETNA-AF-Europe study. Eur Heart J Cardiovasc Pharmacother. 2021;7:f30–39. PubMed PMC

Kirchhof P., Pecen L., Bakhai A., et al. Edoxaban for stroke prevention in atrial fibrillation and age-adjusted predictors of clinical outcomes in routine clinical care. Eur Heart J Cardiovasc Pharmacother. 2022;9:47–57. PubMed PMC

Bohm M., Ezekowitz M.D., Connolly S.J., et al. Changes in renal function in patients with atrial fibrillation: an analysis from the RE-LY trial. J Am Coll Cardiol. 2015;65:2481–2493. PubMed

Cockcroft D.W., Gault M.H. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41. PubMed

Edoxaban Summary of product characteristics. 2015. https://www.ema.europa.eu/en/documents/product-information/lixiana-epar-product-information_en.pdf

Sitticharoenchai P., Takkavatakarn K., Boonyaratavej S., et al. Non-vitamin K antagonist oral anticoagulants provide less adverse renal outcomes than warfarin in non-valvular atrial fibrillation: a systematic review and MetaAnalysis. J Am Heart Assoc. 2021;10 PubMed PMC

Wheeler D.S., Giugliano R.P., Rangaswami J. Anticoagulation-related nephropathy. J Thromb Haemost. 2016;14:461–467. PubMed

Bohula E.A., Giugliano R.P., Ruff C.T., et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 trial. Circulation. 2016;134:24–36. PubMed

Potpara T.S., Ferro C.J., Lip G.Y.H. Use of oral anticoagulants in patients with atrial fibrillation and renal dysfunction. Nat Rev Nephrol. 2018;14:337–351. PubMed

Patti G., Lucerna M., Cavallari I., et al. Insulin-requiring versus noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF. J Am Coll Cardiol. 2017;69:409–419. PubMed

Verdoodt A., Honore P.M., Jacobs R., et al. Do statins induce or protect from acute kidney injury and chronic kidney disease: an update review in 2018. J Transl Int Med. 2018;6:21–25. PubMed PMC

Hu P.J., Wu M.Y., Lin T.C., et al. Effect of statins on renal function in chronic kidney disease patients. Sci Rep. 2018;8 PubMed PMC

Waters D.D. LDL-cholesterol lowering and renal outcomes. Curr Opin Lipidol. 2015;26:195–199. PubMed

Fordyce C.B., Hellkamp A.S., Lokhnygina Y., et al. On-treatment outcomes in patients with worsening renal function with rivaroxaban compared with warfarin: insights from ROCKET AF. Circulation. 2016;134:37–47. PubMed

Hijazi Z., Hohnloser S.H., Andersson U., et al. Efficacy and safety of apixaban compared with warfarin in patients with atrial fibrillation in relation to renal function over time: insights from the ARISTOTLE randomized clinical trial. JAMA Cardiol. 2016;1:451–460. PubMed