Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection

Masaki Murata; Mitsushige Sugimoto; Satoshi Ueshima; Yasuaki Nagami; Masaki Ominami; Manabu Sawaya; Yasuki Nakatani; Yohei Furumoto; Osamu Dohi; Tetsuya Sumiyoshi; Masakatsu Fukuzawa; Shigetsugu Tsuji; Koji Miyahara; Yoji Takeuchi; Sho Suzuki; Naoyuki Tominaga; Nobuaki Yagi; Satoshi Osawa; Yasuhisa Sakata; Takanori Yamada; Yashiro Yoshizawa; Atsushi Yamauchi; Takeshi Yamamura; Shunichiro Orihara; Shin'ichi Miyamoto; Sayana Matsuda; Daiki Hira; Tomohiro Terada; Toshiya Katsura; Takuji Gotoda; Mitsuhiro Fujishiro; Takashi Kawai

doi:10.1016/j.gie.2023.11.048

Association of direct oral anticoagulant and delayed bleeding with pharmacokinetics after endoscopic submucosal dissection

Gastrointest Endosc. 2024 May;99(5):721-731.e4. doi: 10.1016/j.gie.2023.11.048. Epub 2023 Dec 1.

Authors

Masaki Murata¹, Mitsushige Sugimoto², Satoshi Ueshima³, Yasuaki Nagami⁴, Masaki Ominami⁴, Manabu Sawaya⁵, Yasuki Nakatani⁶, Yohei Furumoto⁷, Osamu Dohi⁸, Tetsuya Sumiyoshi⁹, Masakatsu Fukuzawa¹⁰, Shigetsugu Tsuji¹¹, Koji Miyahara¹², Yoji Takeuchi¹³, Sho Suzuki¹⁴, Naoyuki Tominaga¹⁵, Nobuaki Yagi¹⁶, Satoshi Osawa¹⁷, Yasuhisa Sakata¹⁸, Takanori Yamada¹⁹, Yashiro Yoshizawa²⁰, Atsushi Yamauchi²¹, Takeshi Yamamura²², Shunichiro Orihara²³, Shin'ichi Miyamoto¹, Sayana Matsuda³, Daiki Hira²³, Tomohiro Terada²⁴, Toshiya Katsura³, Takuji Gotoda²⁵, Mitsuhiro Fujishiro²⁶, Takashi Kawai²⁷

Affiliations

¹ Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
² Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan; Division of Genome-Wide Infectious Microbiology, Research Center for GLOBAL and LOCAL Infectious Disease, Oita University, Oita, Japan. Electronic address: sugimo@oita-u.ac.jp.
³ College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
⁴ Department of Gastroenterology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan.
⁵ Department of Gastroenterology, Graduate School of Medicine, Hirosaki University, Aomori, Japan.
⁶ Department of Gastroenterology and Hepatology, Japanese Red Cross Wakayama Medical Center, Wakayama, Japan.
⁷ Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
⁸ Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
⁹ Department of Gastroenterology, Tonan Hospital, Hokkaido, Japan.
¹⁰ Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan.
¹¹ Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan.
¹² Department of Internal Medicine, Hiroshima City Hospital, Hiroshima, Japan.
¹³ Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁴ Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; Department of Gastroenterology and Hepatology, International University of Health and Welfare, School of Medicine, Chiba, Japan.
¹⁵ Department of Gastroenterology, Saga-Ken Medical Centre Koseikan, Saga, Japan.
¹⁶ Department of Gastroenterology, Asahi University Hospital, Gifu, Japan.
¹⁷ Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
¹⁸ Department of Gastroenterology, Saga University Hospital, Saga, Japan.
¹⁹ Department of Gastroenterology, Iwata City Hospital, Shizuoka, Japan.
²⁰ Department of Gastroenterology, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
²¹ Department of Gastroenterology and Hepatology, Kitano Hospital, Osaka, Japan.
²² Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan.
²³ Department of Health Data Science, Tokyo Medical University Hospital, Tokyo, Japan.
²⁴ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
²⁵ Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan.
²⁶ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²⁷ Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan.

PMID: 38042206
DOI: 10.1016/j.gie.2023.11.048

Abstract

Background and aims: Pharmacokinetic parameters, such as drug plasma level at trough, time to maximum plasma concentration (T_max), and coagulation factor Xa (FXa) activity generally predict factors for the anticoagulant effects of direct oral anticoagulants (DOACs). Although GI bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about the association between post-ESD bleeding in patients taking DOACs and the pharmacologic parameters. This study aimed to evaluate pharmacologic risk factors for post-ESD bleeding in patients taking DOACs.

Methods: We prospectively evaluated the incidence of post-ESD bleeding in patients taking DOACs between April 2018 and May 2022 at 21 Japanese institutions and investigated the association with post-ESD bleeding and pharmacologic factors, including plasma concentration and FXa activity at trough and T_max.

Results: The incidence of post-ESD bleeding was 12.8% (14 of 109; 95% confidence interval [CI], 7.2-20.6). Although plasma DOAC concentration and plasma level/dose ratio at trough and T_max varied widely among individuals, a significant correlation with plasma concentration and FXa activity was observed (apixaban: correlation coefficient, -0.893; P < .001). On multivariate analysis, risk factors for post-ESD bleeding in patients taking DOACs were higher age (odds ratio [OR], 1.192; 95% CI, 1.020-1.392; P = .027) and high anticoagulant ability analyzed by FXa activity at trough and T_max (OR, 6.056; 95% CI, 1.094-33.529; P = .039).

Conclusions: The incidence of post-ESD bleeding in patients taking DOACs was high, especially in older patients and with high anticoagulant effects of DOACs. Measurement of pharmacokinetic parameters of DOACs may be useful in identifying patients at higher risk of post-ESD bleeding.