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Edoxaban versus Vitamin K Antagonist for Atrial Fibrillation after TAVR - nejm.org

Abstract

Background

The role of direct oral anticoagulants as compared with vitamin K antagonists for atrial fibrillation after successful transcatheter aortic-valve replacement (TAVR) has not been well studied.

Methods

We conducted a multicenter, prospective, randomized, open-label, adjudicator-masked trial comparing edoxaban with vitamin K antagonists in patients with prevalent or incident atrial fibrillation as the indication for oral anticoagulation after successful TAVR. The primary efficacy outcome was a composite of adverse events consisting of death from any cause, myocardial infarction, ischemic stroke, systemic thromboembolism, valve thrombosis, or major bleeding. The primary safety outcome was major bleeding. On the basis of a hierarchical testing plan, the primary efficacy and safety outcomes were tested sequentially for noninferiority, with noninferiority of edoxaban established if the upper boundary of the 95% confidence interval for the hazard ratio did not exceed 1.38. Superiority testing of edoxaban for efficacy would follow if noninferiority and superiority were established for major bleeding.

Results

A total of 1426 patients were enrolled (713 in each group). The mean age of the patients was 82.1 years, and 47.5% of the patients were women. Almost all the patients had atrial fibrillation before TAVR. The rate of the composite primary efficacy outcome was 17.3 per 100 person-years in the edoxaban group and 16.5 per 100 person-years in the vitamin K antagonist group (hazard ratio, 1.05; 95% confidence interval [CI], 0.85 to 1.31; P=0.01 for noninferiority). Rates of major bleeding were 9.7 per 100 person-years and 7.0 per 100 person-years, respectively (hazard ratio, 1.40; 95% CI, 1.03 to 1.91; P=0.93 for noninferiority); the difference between groups was mainly due to more gastrointestinal bleeding with edoxaban. Rates of death from any cause or stroke were 10.0 per 100 person-years in the edoxaban group and 11.7 per 100 person-years in the vitamin K antagonist group (hazard ratio, 0.85; 95% CI, 0.66 to 1.11).

Conclusions

In patients with mainly prevalent atrial fibrillation who underwent successful TAVR, edoxaban was noninferior to vitamin K antagonists as determined by a hazard ratio margin of 38% for a composite primary outcome of adverse clinical events. The incidence of major bleeding was higher with edoxaban than with vitamin K antagonists. (Funded by Daiichi Sankyo; ENVISAGE-TAVI AF ClinicalTrials.gov number, NCT02943785. opens in new tab .)

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Funding and Disclosures

Supported by Daiichi Sankyo.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on August 28, 2021, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

We thank Wei Jiang, Ph.D., Robert Crozier, Ph.D., Wolfgang Deschle, M.S.Pharm., JoAnne DiAgostino, M.S., Tetsuya Kimura, M.S., Yong Lin, Ph.D., Teresa Reyes, B.S., Kumiko Sugio, M.S., Sabine Köhler, Ph.D., and Hideki Ichikawa for their critical contributions to this work; and Margaret Van Horn, Ph.D., of AlphaBioCom for medical writing and editorial assistance with an earlier version of the manuscript.

Author Affiliations

From the Department of Cardiology, Erasmus University Medical Center, Thoraxcenter, Rotterdam, the Netherlands (N.M.V.M., E.B.); Daiichi Sankyo, Basking Ridge, NJ (M.U., J.J., A.D., C.C.); the Department of Internal Medicine II, Division of Cardiology, Vienna General Hospital, Medical University, Vienna (C.H., I.L.); the Department of Internal Medicine, St. Johannes Hospital, Dortmund (H.M.), the Department of Internal Medicine I, University Hospital Würzburg, Würzburg (P.N.), the Department of Internal Medicine–Cardiology, Heart Center Leipzig at University of Leipzig, Leipzig (H.T.), Bremer Institute for Heart and Circulation Research at Klinikum Links der Weser, Bremen (R.H.), the Department of Cardiology, Asklepios Klinik St. Georg, Hamburg (F.M.), Daiichi Sankyo Europe, Munich (P.L., H.L.), the Department of Neurology, Alfried Krupp Krankenhaus, Essen (R.V.), and the Department of Neurology, University Hospital Heidelberg, Heidelberg (R.V.) — all in Germany; Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Hospital, New York (R. Mehran, G.D.D.); the Department of Cardiology, Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela (D.L.-O.), the Cardiovascular Institute, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (L.N.-F.), the Department of Cardiology, University Hospital La Paz (R. Moreno), and the Department of Cardiology, University Hospital Ramon y Cajal (J.L.Z.), Madrid — all in Spain; the Department of Cardiology, Washington Adventist Hospital, Takoma Park, MD (F.S.); the Department of Cardiology, Toyohashi Heart Center, Toyohashi (M.Y.), the Department of Cardiology, Teikyo University School of Medicine (Y.W.), and the Department of Cardiology, Keio University School of Medicine (K.H.), Tokyo, and the Division of Cardiology and Catheterization Laboratories, Shonan Kamakura General Hospital, Kamakura (S.S.) — all in Japan; the Department of Cardiology, Jessa Hospital, Hasselt, Belgium (P.V.); Quebec Heart and Lung Institute, Laval University, Quebec, QC, Canada (J.R.-C.); the Division of Cardiovascular Medicine, University Hospital of Strasbourg, Strasbourg, France (P.O.); the Division of Cardiology, Policlinico Hospital, University of Catania, Catania, Italy (P.C.); the Department of Internal Medicine, Cardiovascular Center, Seoul National University Hospital, Seoul, South Korea (H.-S.K.); the Department of Cardiology, University of Bern, Bern (T.P.), and Cardiocentro Ticino Institute and Department of Biomedical Sciences, University of Italian Switzerland, Lugano (M.V.) — both in Switzerland; the Department of Cardiology, University Hospital of Wales, Cardiff (R.A.), and the Division of Brain Sciences, Imperial College London, London (R.V.) — both in the United Kingdom; the Cardiology Section, University of Oklahoma Health Sciences Center, Oklahoma City (U.B.); and National and Kapodistrian University of Athens, School of Medicine, Athens (G.D.D.).

Address reprint requests to Dr. Dangas at the Division of Cardiology, Mount Sinai Medical Center, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl., Box 1030, New York, NY 10029, or at [email protected]

The ENVISAGE-TAVI AF Investigators are listed in the Supplementary Appendix, available at NEJM.org.