Pharmacodynamics of direct oral anticoagulants associated with post-endoscopic delayed mucosal resection bleeding of colorectal neoplasms

Masaki Murata¹, Mitsushige Sugimoto^{2

3}, Satoshi Ueshima⁴, Yasuaki Nagami⁵, Masaki Ominami⁵, Yohei Furumoto⁶, Tatsuya Mikami⁷, Manabu Sawaya⁸, Naohisa Yoshida⁹, Ken Inoue⁹, Yasuhiko Maruyama¹⁰, Tomohiro Terai¹⁰, Shigetsugu Tsuji¹¹, Takeshi Yamamura¹², Takanori Yamada^{13

14}, Yoji Takeuchi¹⁵, Nobuaki Yagi¹⁶, Satoshi Osawa¹⁴, Yashiro Yoshizawa¹⁷, Shunichiro Orihara¹⁸, Shin'ichi Miyamoto¹, Sayana Matsuda⁴, Daiki Hira¹⁹, Tomohiro Terada¹⁹, Toshiya Katsura⁴, Mitsuhiro Fujishiro²⁰, Takashi Kawai²¹

Affiliations

¹ Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
² Division of Genome-Wide Infectious Diseases, Research Center for GLOBAL and LOCAL Infectious Disease, Oita University, Oita, Japan. sugimo@oita-u.ac.jp.
³ Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan. sugimo@oita-u.ac.jp.
⁴ College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
⁵ Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
⁶ Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
⁷ Division of Endoscopy, Hirosaki University Hospital, Aomori, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, Hirosaki University, Aomori, Japan.
⁹ Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁰ Department of Gastroenterology, Fujieda Municipal General Hospital, Shizuoka, Japan.
¹¹ Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan.
¹² Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan.
¹³ Department of Gastroenterology, Iwata City Hospital, Shizuoka, Japan.
¹⁴ Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
¹⁵ Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁶ Department of Gastroenterology, Asahi University Hospital, Gifu, Japan.
¹⁷ Department of Gastroenterology, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
¹⁸ Department of Health Data Science, Tokyo Medical University, Tokyo, Japan.
¹⁹ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
²⁰ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²¹ Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan.

PMID: 41429902
PMCID: PMC12749976
DOI: 10.1038/s41598-025-33056-w

Pharmacodynamics of direct oral anticoagulants associated with post-endoscopic delayed mucosal resection bleeding of colorectal neoplasms

Masaki Murata et al. Sci Rep. 2025.

. 2025 Dec 22;15(1):45129.

doi: 10.1038/s41598-025-33056-w.

Authors

Affiliations

¹ Department of Gastroenterology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan.
² Division of Genome-Wide Infectious Diseases, Research Center for GLOBAL and LOCAL Infectious Disease, Oita University, Oita, Japan. sugimo@oita-u.ac.jp.
³ Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan. sugimo@oita-u.ac.jp.
⁴ College of Pharmaceutical Sciences, Ritsumeikan University, Shiga, Japan.
⁵ Department of Gastroenterology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
⁶ Department of Gastroenterology, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
⁷ Division of Endoscopy, Hirosaki University Hospital, Aomori, Japan.
⁸ Department of Gastroenterology, Graduate School of Medicine, Hirosaki University, Aomori, Japan.
⁹ Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
¹⁰ Department of Gastroenterology, Fujieda Municipal General Hospital, Shizuoka, Japan.
¹¹ Department of Gastroenterology, Ishikawa Prefectural Central Hospital, Ishikawa, Japan.
¹² Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Aichi, Japan.
¹³ Department of Gastroenterology, Iwata City Hospital, Shizuoka, Japan.
¹⁴ Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
¹⁵ Department of Gastrointestinal Oncology, Osaka International Cancer Institute, Osaka, Japan.
¹⁶ Department of Gastroenterology, Asahi University Hospital, Gifu, Japan.
¹⁷ Department of Gastroenterology, Seirei Hamamatsu General Hospital, Shizuoka, Japan.
¹⁸ Department of Health Data Science, Tokyo Medical University, Tokyo, Japan.
¹⁹ Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
²⁰ Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
²¹ Center for Health Surveillance & Preventive Medicine, Tokyo Medical University Hospital, Tokyo, Japan.

PMID: 41429902
PMCID: PMC12749976
DOI: 10.1038/s41598-025-33056-w

Abstract

Anticoagulant effects of direct oral anticoagulants (DOACs) are influenced by their plasma levels and anti-factor Xa (FXa) activity. Delayed bleeding is a major adverse event associated with endoscopic mucosal resection (EMR) of colorectal neoplasms. However, the association between post-EMR bleeding and pharmacodynamics in patients taking DOAC remains unknown. This study investigated the association between pharmacological risk factors and delayed bleeding in patients receiving DOAC. This multicenter prospective trial in Japan evaluated the incidence of post-EMR delayed bleeding in DOAC users between April 2018 and May 2022 and determined the association of post-EMR delayed bleeding with plasma levels and FXa activity. The incidence of post-EMR delayed bleeding was 10.5% (95% confidence interval [CI]: 5.3%-18.0%). There were large individual differences in plasma levels and FXa activity for each DOAC. At the trough and T_max, plasma DOAC levels and plasma level/dose ratios were significantly correlated with FXa activity. Multivariate analysis showed that high anticoagulant ability was a risk factor for post-EMR delayed bleeding (adjusted OR, 12.211; 95% CI: 1.081-137.922, p = 0.043). DOAC users with high anticoagulant activity may be at higher risk of post-EMR delayed bleeding from colorectal neoplasms.

Supplementary Information: The online version contains supplementary material available at 10.1038/s41598-025-33056-w.

Keywords: Bleeding; Direct oral anticoagulant; Endoscopic mucosal resection; Pharmacokinetics; Polymorphism.

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Conflict of interest statement

Declarations. Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The study protocol conformed to the ethical guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board of each institution (approved number in Tokyo Medical University: T2020-0025). Written informed consent was obtained from all patients. The registry number for this clinical trial was UMIN000042576 at the University Hospital Medical Information Network.

Figures

**Fig. 1**
Association of plasma DOAC level at the trough with time to maximum plasma concentration (A) and of plasma concentration/dose ratio at the trough with plasma concentration/dose ratio at maximum plasma concentration (B). Abbreviations: DOAC, direct oral anticoagulant; C/D, plasma concentration/dose; T_max, time to maximum plasma concentration.

**Fig. 2**
Correlation of plasma DOAC level with FXa activity for apixaban (A), edoxaban (B) and rivaroxaban (C). Abbreviations: DOAC, direct oral anticoagulant; EMR, endoscopic mucosal resection.

**Fig. 3**
Association of FXa activity at the trough with FXa activity at maximum plasma concentration in patients with and without post-EMR bleeding. Abbreviations: DOAC, direct oral anticoagulant; EMR, endoscopic mucosal resection.

See this image and copyright information in PMC

References

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Pharmacodynamics of direct oral anticoagulants associated with post-endoscopic delayed mucosal resection bleeding of colorectal neoplasms

Affiliations

Pharmacodynamics of direct oral anticoagulants associated with post-endoscopic delayed mucosal resection bleeding of colorectal neoplasms

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

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Full Text Sources

Medical

Miscellaneous