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Randomized Controlled Trial
. 2021 Apr:86:294-300.
doi: 10.1016/j.jocn.2020.10.036. Epub 2021 Jan 12.

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial

Sarah E Nelson  1 , Robert P Giugliano  2 , Elliott M Antman  3 , Jeong-Gun Park  4 , Andrew D Norden  5 , Natalia S Rost  6 , Scott Silverman  7 , Aneesh B Singhal  8 , Hans J Lanz  9 , Eugene Braunwald  10 , Christian T Ruff  11 ; ENGAGE AF-TIMI 48 Steering Committee and Investigators
Affiliations
Randomized Controlled Trial

Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation with warfarin or edoxaban: An in-depth analysis from the ENGAGE AF-TIMI 48 randomized trial

Sarah E Nelson et al. J Clin Neurosci. 2021 Apr.

Abstract

Intracranial hemorrhage (ICH) is a known risk of oral anticoagulation; delineating ICH attributes may provide nuanced guidance regarding atrial fibrillation management. We evaluated ICH characteristics and outcomes from Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48), a randomized trial that compared two edoxaban regimens (higher-dose edoxaban regimen 60/30 mg (HDER), lower-dose edoxaban regimen 30/15 mg (LDER)) with warfarin in patients with atrial fibrillation. Patients who suffered ICH vs those who did not were compared and independent predictors of ICH were calculated. We also assessed ICH subtype and etiology. Of 21,105 randomized patients, 322 (1.53%) had ≥ 1 ICH for a total of 368 events. Intraparenchymal hemorrhage (HDER: HR 0.52 [95% CI 0.35-0.77], LDER: HR 0.22 [0.13-0.38]) and subdural hematoma (HDER: HR 0.29 [0.15-0.55], LDER: HR 0.26 [0.13-0.50]) were lower with both HDER and LDER vs warfarin. Subarachnoid hemorrhage frequency was similar in the HDER vs warfarin groups but lower in LDER. Compared to warfarin, edoxaban was associated with lower risk of spontaneous ICH (HDER: HR 0.47 [0.31-0.69], LDER: HR 0.34 [0.22-0.53]) and traumatic ICH (HDER: HR 0.32 [0.17-0.61], LDER: HR 0.31 [0.16-0.59]). In multivariable analysis, randomization to warfarin, increased age, and risk of falling remained independent predictors of ICH. In ENGAGE AF-TIMI 48, ICH was decreased in edoxaban-treated patients compared to warfarin-treated patients, including ICH of both spontaneous and traumatic causes. Both edoxaban regimens lowered intraparenchymal and subdural hemorrhages compared to warfarin. Patient characteristics and medical history may help guide anticoagulation management.

Keywords: Anticoagulation; Atrial fibrillation; Intracranial hemorrhage.

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Conflict of interest statement

Declaration of Competing Interest S.E.N. has received compensation from Springer Nature and grant funding from the Brain Aneurysm Foundation. RPG: Dr. Giugliano reports grants from Daiichi Sankyo, during the conduct of the study; personal fees from Akcea, personal fees from Amarin, personal fees from American College of Cardiology, grants and personal fees from Amgen, personal fees from Angel Med, personal fees from Beckman-Coulter, personal fees from Boeringer-Ingelheim, personal fees from Bristol Myers Squibb, personal fees from CVS Caremark, grants and personal fees from Daiichi Sankyo, personal fees from GlaxoSmithKline, personal fees from Janssen, personal fees from Lexicon, grants and personal fees from Merck, personal fees from Portola, personal fees from Pfizer, personal fees from St Jude, personal fees from Stealth Peptide, outside the submitted work; and Institutional research grant to the TIMI Study Group at Brigham and Women's Hospital for research he is not directly involved in from AstraZeneca; Bayer; Eisai; GlaxoSmithKline; Intarcia; Janssen Research and Development; Medicines Company; MedImmune; Novartis; Poxel; Pfizer; Quark Pharmaceuticals; Takeda. EMA: Dr. Antman reports receiving grant support through his institution from Daiichi Sankyo. JGP: Dr. Park reports no conflicts of interest. ADN: Dr. Norden reports that he is an employee and shareholder of COTA, Inc. NSR: Dr. Rost reports no conflicts of interest. SS: Dr. Silverman reports no conflicts of interest. ABS: Dr. Singhal reports grant support through his institution (Massachusetts General Hospital) from Boehringer-Ingelheim; research support from the NIH (grant numbers U10 NS086729, U01NS095869, R01NS105875 and R01DC012584); research support from Dana Foundation; stock and/or stock options from Biogen and Zafgen; consulting fees from Omniox, and honoraria from Medlink, Wolters-Kluwer Health, and UptoDate. HJL: Dr. Lanz is an employee of Daiichi Sankyo. EB: Dr. Braunwald reports grant support through his institution from Daiichi Sankyo, Astra Zeneca, Glaxo SmithKline, Merck, Duke University, Novartis, and the Medicines company; consulting fees from Cardurion, MyoKardia, Sanofi, and Verve; lecture fees from Medscape; uncompensated consultancies and lectures for Merck, the Medicines company, and Novartis. CTR: Dr. Ruff reports grant support through his institution (Brigham and Women’s Hospital) from Daiichi Sankyo and has served as a consultant and received honoraria from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Pfizer, Janssen and Portola; and grant support through his institution outside the submitted work from MedImmune, NIH and Boehringer Ingelheim.

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